1. |
- Portelius, Erik, 1977, et al.
(författare)
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A novel pathway for amyloid precursor protein processing.
- 2011
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 32:6, s. 1090-98
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid precursor protein (APP) can be proteolytically processed along two pathways, the amyloidogenic that leads to the formation of the 40-42 amino acid long Alzheimer-associated amyloid beta (Abeta) peptide and the non-amyloidogenic in which APP is cut in the middle of the Abeta domain thus precluding Abeta formation. Using immunoprecipitation and mass spectrometry we have shown that Abeta is present in cerebrospinal fluid (CSF) as several shorter isoforms in addition to Abeta1-40 and Abeta1-42. To address the question by which processing pathways these shorter isoforms arise, we have developed a cell model that accurately reflects the Abeta isoform pattern in CSF. Using this model, we determined changes in the Abeta isoform pattern induced by alpha-, beta-, and gamma-secretase inhibitor treatment. All isoforms longer than and including Abeta1-17 were gamma-secretase dependent whereas shorter isoforms were gamma-secretase independent. These shorter isoforms, including Abeta1-14 and Abeta1-15, were reduced by treatment with alpha- and beta-secretase inhibitors, which suggests the existence of a third and previously unknown APP processing pathway involving concerted cleavages of APP by alpha- and beta-secretase.
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2. |
- Andersson K, Pernille, et al.
(författare)
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The How, What, and Why of Digitalizing Physical Retail Spaces
- 2019
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Ingår i: The 16th International Research Symposium on Advancing Service Research and Practice.
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Konferensbidrag (refereegranskat)abstract
- This aim of this study is to enhance the understanding of customer behavior and customer experience in the context of city centers and peripheral shopping centers and how the use of digitalized services affects this experience. In this paper we adopt a qualitative approach to explore consumers´ activities when visiting a city and/or a shopping center and the experiences connected to the visit. The study is based on data from 832 (55% female) with a M age = 48 years (range 17-91 years) consumers.When visiting a city center and/or a shopping center, customers engage with a variety of different touchpoints (Socchi, Hart and Haji, 2016). From a customer perspective these touchpoints create experiences that generates many types of values. In recent years, the mass media has warned for the demise of city and shopping centers commerce. This purported demise is mainly due to the strong growth of e-commerce. To meet this competition, the retail and hospitality industry has developed strategies to create new customer experiences and thus attract customers back to the city center’s physical places. As a consequence of the technical development, companies frequently try to influence customers’ experiences through various digitalized services, where these digitalized service have the potential to improve customer experience by providing superior and personalized services (Roy et al. 2016). The question is what impact such services have on customers’ experiences and how this, in turn, affects the profitability of the retail and hospitality industry as a whole.In order to shed light on the activities and experiences of visitors to city and shopping centers regular consumers were approach during a regular visit to such an area and asked to answer a few open ended questions. The data was analyzed using thematic analysis. Thematic analysis aims to identify and report on thematic patterns across the sample, which allows researchers to make interpretations of the data that reflect the reported reality of participants (Braun and Clarke, 2006; Hayes, 2000; Ruane and Wallace, 2013).The preliminary analysis of the data shows a variety of activities and touchpoints when visiting the city and shopping center. Seven themes emerged in our analysis of the participants´ responses: Relationship, Goal fulfillment, Experiences, Physical venue, Milieu, Practical usability and Non-intrusive.In order to make more sense of the seven themes a model were developed. In this model three of the themes were connected to the customer, two connected to the service provider and the last two connected to digital technology. These three clusters interact in different ways.The customer cluster contains the themes relationships, goal fulfilment and experiences. The themes in this cluster describe and vivifies the customer. The customer is not just a “shopping robot” jumping from touchpoint to touchpoint along a customer journey. The customer instead is a person with goals to fulfil but at the same time someone who has a great need of relationships on different levels and a person who will and want to experience things.The service provider cluster contains two themes. One were named physical venue and this is where the service provider, be it a storeowner or a restaurant owner for example, has the most direct control. It is also where the customer will go to fulfil his or her goals. Here the direct contact between customer and service provider can and will take place. The second theme in this cluster were named “milieu”. The milieu can be the space the customer needs to pass in order to get to the physical venue or other factors that the service provider do not have control over (e.g. public spaces and weather)The third and most interesting cluster concerns the digital technology, named practical usability and non-intrusive. Digitalization is highly interesting when it comes to the relationship between the customer and the service provider. The first theme described the importance of the usefulness of digital technology, and in regards to digitalization the results indicates that digitalized services mostly fulfill utilitarian needs and works best in functional touchpoints. The theme called non-intrusive describes the relation between the customer and the digital technology. It may be somewhat drastic to talk about a two edged sword but on the one hand digital technology makes life easier and sometimes more joyful and at the same time the technology may disturb goal activities which leads to negative experiences.These findings is important because it offers help to those managing city and shopping centers in identify touchpoints that need to be digitalized and those who need to be reinforced through social activities This knowledge could also help managers develop strategies to create new customer experience, i.e. create good valuescapes, and thus tease customer back to the city and shopping center´s physical places.REFERENCESBraun, V. and Clarke, V., (2006), 'Using thematic analysis in psychology’, Qualitative Research in Psychology, 3 (2) 77-101Hayes, N. (2000), Doing Psychological Research, Open University Press, Buckinghamshire.Ruane, L. and Wallace, E., (2013), 'Generation Y females online: insight from brand narratives', Qualitative Market Research: An International Journal, 16 (3) 315-335Roy, S. K., Balaji, M. S., Sadeque, S., Nguyen, B., and Mlewar, T. C., (2016), 'Constituents and consequences of smart customer experience in retailing', Technological Forecasting and Social Change, 124 257-270Stocchi, L., Hart, C., and Haji, I., (2016), 'Understanding the town centre customer experience (TCCE) ', Journal of Marketing Management, 32 (17-18) 1562-1587
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3. |
- Bager, Jessica, et al.
(författare)
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Prevalence and early-life risk factors for tree nut sensitization and allergy in young adults
- 2021
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Ingår i: Clinical and Experimental Allergy. - : John Wiley & Sons. - 0954-7894 .- 1365-2222. ; 51:11, s. 1429-1437
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Tidskriftsartikel (refereegranskat)abstract
- Background Tree nut allergy may cause anaphylaxis. There are limited population-based studies on prevalence and early-life risk factors. Methods We evaluated the prevalence of reported symptoms and allergic sensitization to tree nuts at age 24 years in the BAMSE population-based cohort study and assessed early-life factors associated with the development of tree nut allergy. We estimated tree nut allergy prevalence, by analysing questionnaire data on tree nut ingestion and symptoms at age 12, 16 and 24 years, and IgE sensitization at age 24 years to hazelnut, walnut, pecan, cashew, pistachio, Brazil nut, almond extracts and allergen molecules Cor a 1, 9, 14 (hazelnut), Jug r 1 (walnut) and Ana o 3 (cashew). We evaluated eczema, asthma, food allergies, inherited risk of allergy and gender as potential early-life risk factors. Results Data were available for 2215/4089 (54%) BAMSE study participants, for estimation of the prevalence of tree nut sensitization (21.2%), tree nut allergy symptoms (9.8%) and combined sensitization and symptoms (7.9%, 2.1% for storage protein sensitization and symptoms, 4.3% for any sensitization and non-mild symptoms). Sixty-three per cent of sensitized individuals (295/470) were asymptomatic, but only 76/470 (16%) storage protein sensitized individuals. Egg allergy (ORadj 8.50 95% CI 2.15-33.6), eczema (ORadj 2.53 95% CI 1.21-5.32) and asthma (ORadj 5.59 95% CI 2.35-13.3)) at pre-school age were associated with future development of tree nut symptoms and storage protein sensitization. At age 24 years, tree nut allergy was associated with current eczema and with markers of current asthma severity. Sensitization to storage proteins was more strongly associated with symptoms than sensitization to whole extract for all tree nuts evaluated. Conclusions In this Swedish cohort, we found tree nut whole extract sensitization is common but usually asymptomatic. Storage protein sensitization is a more reliable indicator of tree nut symptoms. Tree nut allergy is associated with early onset, persistent and severe atopic disease.
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4. |
- Bergman, Erik, et al.
(författare)
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A full-document analysis of the semantic relation between European Public Assessment Reports and EMA guidelines using a BERT language model
- 2023
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:12
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Tidskriftsartikel (refereegranskat)abstract
- In the European Union, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) develop guidelines to guide drug development, supporting development of efficacious and safe medicines. A European Public Assessment Report (EPAR) is published for every medicine application that has been granted or refused marketing authorisation within the EU. In this work, we study the use of text embeddings and similarity metrics to investigate the semantic similarity between EPARs and EMA guidelines. All 1024 EPARs for initial marketing authorisations from 2008 to 2022 was compared to the 669 current EMA scientific guidelines. Documents were converted to plain text and split into overlapping chunks, generating 265,757 EPAR and 27,649 guideline text chunks. Using a Sentence BERT language model, the chunks were transformed into embeddings and fed into an in-house piecewise matching algorithm to estimate the full-document semantic distance. In an analysis of the document distance scores and product characteristics using a linear regression model, EPARs of anti-virals for systemic use (ATC code J05) and antihemorrhagic medicines (B02) present with statistically significant lower overall semantic distance to guidelines compared to other therapeutic areas, also when adjusting for product age and EPAR length. In conclusion, we believe our approach provides meaningful insight into the interplay between EMA scientific guidelines and the assessment made during regulatory review, and could potentially be used to answer more specific questions such as which therapeutic areas could benefit from additional regulatory guidance.
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5. |
- Bergman, Erik, et al.
(författare)
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A natural language processing approach towards harmonisation of European medicinal product information
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:10
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Tidskriftsartikel (refereegranskat)abstract
- Product information (PI) is a vital part of any medicinal product approved for use within the European Union and consists of a summary of products characteristics (SmPC) for healthcare professionals and package leaflet (PL) for patients, together with the product packaging. In this study, based on the English corpus of the EMA product information documents for all centrally approved medicinal products within the EU, a BERT sentence embedding model was used together with clustering and dimensional reduction techniques to identify sentence similarity clusters that could be candidates for standardization. A total of 1258 medicinal products were included in the study. From these, a total of 783 K sentences were extracted from SmPC and PL documents which were aggregated into a total of 284 and 129 semantic similarity clusters, respectively. The spread distribution among clusters shows separation into different cluster types. Examples of clusters with low spread include those with identical word embeddings due to current standardization, such as section headings and standard phrases. Others show minor linguistic variations, while the group with the largest variability contains variable wording but with significant semantic overlap. The sentence clusters identified could serve as candidates for further standardization of the PI. Moving from free text human wording to auto-generated text elements based on multiple-choice input for appropriate parts of the package leaflet and summary of product characteristics, could reduce both time and complexity for applicants as well as regulators, and ultimately provide patients and prescribers with documents that are easier to understand and better adapted for search availabilities.
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6. |
- Bergman, Erik, et al.
(författare)
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BERT based natural language processing for triage of adverse drug reaction reports shows close to human-level performance
- 2023
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Ingår i: PLOS Digital Health. - : Public Library of Science (PLoS). - 2767-3170. ; 2:12
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Tidskriftsartikel (refereegranskat)abstract
- Post-marketing reports of suspected adverse drug reactions are important for establishing the safety profile of a medicinal product. However, a high influx of reports poses a challenge for regulatory authorities as a delay in identification of previously unknown adverse drug reactions can potentially be harmful to patients. In this study, we use natural language processing (NLP) to predict whether a report is of serious nature based solely on the free-text fields and adverse event terms in the report, potentially allowing reports mislabelled at time of reporting to be detected and prioritized for assessment. We consider four different NLP models at various levels of complexity, bootstrap their train-validation data split to eliminate random effects in the performance estimates and conduct prospective testing to avoid the risk of data leakage. Using a Swedish BERT based language model, continued language pre-training and final classification training, we achieve close to human-level performance in this task. Model architectures based on less complex technical foundation such as bag-of-words approaches and LSTM neural networks trained with random initiation of weights appear to perform less well, likely due to the lack of robustness that a base of general language training provides.
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7. |
- Brinkmalm, Gunnar, et al.
(författare)
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An online nano-LC-ESI-FTICR-MS method for comprehensive characterization of endogenous fragments from amyloid β and amyloid precursor protein in human and cat cerebrospinal fluid.
- 2012
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Ingår i: Journal of mass spectrometry : JMS. - : Wiley. - 1096-9888 .- 1076-5174. ; 47:5, s. 591-603
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid precursor protein (APP) is the precursor protein to amyloid β (Aβ), the main constituent of senile plaques in Alzheimer's disease (AD). Endogenous Aβ peptides reflect the APP processing, and greater knowledge of different APP degradation pathways is important to understand the mechanism underlying AD pathology. When one analyzes longer Aβ peptides by low-energy collision-induced dissociation tandem mass spectrometry (MS/MS), mainly long b-fragments are observed, limiting the possibility to determine variations such as amino acid variants or post-translational modifications (PTMs) within the N-terminal half of the peptide. However, by using electron capture dissociation (ECD), we obtained a more comprehensive sequence coverage for several APP/Aβ peptide species, thus enabling a deeper characterization of possible variants and PTMs. Abnormal APP/Aβ processing has also been described in the lysosomal storage disease Niemann-Pick type C and the major large animal used for studying this disease is cat. By ECD MS/MS, a substitution of Asp7 → Glu in cat Aβ was identified. Further, sialylated core 1 like O-glycans at Tyr10, recently discovered in human Aβ (a previously unknown glycosylation type), were identified also in cat cerebrospinal fluid (CSF). It is therefore likely that this unusual type of glycosylation is common for (at least) species belonging to the magnorder Boreoeutheria. We here describe a detailed characterization of endogenous APP/Aβ peptide species in CSF by using an online top-down MS-based method.
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8. |
- Brinkmalm, Gunnar, et al.
(författare)
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Soluble amyloid precursor protein α and β in CSF in Alzheimer's disease.
- 2013
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Ingår i: Brain research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1513, s. 117-26
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral accumulation of amyloid β (Aβ) is a pathological hallmark of Alzheimer's disease (AD). Proteolytic processing of amyloid precursor protein (APP) by α- or β-secretase results in two soluble metabolites, sAPPα and sAPPβ, respectively. However, previous data have shown that both α- and β-secretase have multiple cleavage sites. The aim of this study was to characterize the C-termini of sAPPα and sAPPβ in cerebrospinal fluid (CSF) by mass spectrometry (MS) and to evaluate whether different combinations of these fragments better separate between AD patients and controls by comparing two different sAPP immunoassays. Methods: Using immunoprecipitation and high resolution MS, the APP species present in CSF were investigated. CSF levels of sAPPα and sAPPβ from patients with AD (n=43) and from non-demented controls (n=44) were measured using AlphaLISA and MSD immunoassays that employ different antibodies for C-terminal recognition of sAPPα. Results: Four different C-terminal forms of sAPP were identified, sAPPβ-M671, sAPPβ-Y681, sAPPα-Q686, and sAPPα-K687 (APP770 numbering). Neither immunoassay for the sAPP species could separate the two patient groups. The correlation (R(2)) between the two immunoassays was 0.41 for sAPPα and 0.45 for sAPPβ. Conclusion: Using high resolution MS, we show here for the first time that sAPPα in CSF ends at Q686 and K687. The findings also support the conclusion from several previous studies that sAPPα and sAPPβ levels are unaltered in AD.
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9. |
- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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Explorative and targeted neuroproteomics in Alzheimer's disease.
- 2015
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Ingår i: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002. ; 1854:7, s. 769-778
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a progressive brain amyloidosis that injures brain regions involved in memory consolidation and other higher brain functions. Neuropathologically, the disease is characterized by accumulation of a 42 amino acid peptide called amyloid β (Aβ42) in extracellular senile plaques, intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles, and neuronal and axonal degeneration and loss. Biomarker assays capturing these pathologies have been developed for use on cerebrospinal fluid samples but there are additional molecular pathways that most likely contribute to the neurodegeneration and full clinical expression of AD. One way of learning more about AD pathogenesis is to identify novel biomarkers for these pathways and examine them in longitudinal studies of patients in different stages of the disease. Here, we discuss targeted proteomic approaches to study AD and AD-related pathologies in closer detail and explorative approaches to discover novel pathways that may contribute to the disease. This article is part of a Special Issue entitled: Neuroproteomics: Applications in neuroscience and neurology.
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10. |
- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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Fluid-based proteomics targeted on pathophysiological processes and pathologies in neurodegenerative diseases.
- 2019
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 151:4, s. 417-434
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Tidskriftsartikel (refereegranskat)abstract
- Neurodegenerative dementias constitute a broad group of diseases in which abnormally folded proteins accumulate in specific brain regions and result in tissue reactions that eventually cause neuronal dysfunction and degeneration. Depending on where in the brain this happens, symptoms appear which may be used to classify the disorders on clinical grounds. However, brain changes in neurodegenerative dementias start to accumulate many years prior to symptom onset and there is a poor correlation between the clinical picture and what pathology that is the most likely to cause it. Thus, novel drug candidates having disease-modifying effects that is targeting the underlying pathology and changes the course of the disease needs to be defined using objective biomarker-based measures since the clinical symptoms are often non-specific and overlap between different disorders. Furthermore, the treatment should ideally be initiated as soon as symptoms are evident or when biomarkers confirm an underlying pathology (pre-clinical phase of the disease) to reduce irreversible damage to, for example, neurons, synapses and axons. Clinical trials in the pre-clinical phase bring a greater importance to biomarkers since by definition the clinical effects are difficult or slow to discern in a population that is not yet clinically affected. Here, we discuss neuropathological changes that may underlie neurodegenerative dementias, including how they can be detected and quantified using currently available biofluid-based biomarkers and how more of them could be identified using targeted proteomics approaches.
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