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- Aldrin-Kirk, Patrick, et al.
(author)
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A novel two-factor monosynaptic TRIO tracing method for assessment of circuit integration of hESC-derived dopamine transplants
- 2022
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In: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 17:1, s. 159-172
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Journal article (peer-reviewed)abstract
- Transplantation in Parkinson's disease using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons is a promising future treatment option. However, many of the mechanisms that govern their differentiation, maturation, and integration into the host circuitry remain elusive. Here, we engrafted hESCs differentiated toward a ventral midbrain DA phenotype into the midbrain of a preclinical rodent model of Parkinson's disease. We then injected a novel DA-neurotropic retrograde MNM008 adeno-associated virus vector capsid, into specific DA target regions to generate starter cells based on their axonal projections. Using monosynaptic rabies-based tracing, we demonstrated for the first time that grafted hESC-derived DA neurons receive distinctly different afferent inputs depending on their projections. The similarities to the host DA system suggest a previously unknown directed circuit integration. By evaluating the differential host-to-graft connectivity based on projection patterns, this novel approach offers a tool to answer outstanding questions regarding the integration of grafted hESC-derived DA neurons.
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| 3. |
- Dahlstrand Rudin, Agnes, et al.
(author)
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The neutrophil subset defined by CD177 expression is preferentially recruited to gingival crevicular fluid in periodontitis
- 2021
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In: Journal of Leukocyte Biology. - : WILEY. - 0741-5400 .- 1938-3673. ; 109:2, s. 349-362
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Journal article (peer-reviewed)abstract
- In recent years, the concept of distinct subpopulations of human neutrophils has attracted much attention. One bona fide subset marker, exclusively expressed by a proportion of circulating neutrophils in a given individual, and therefore dividing neutrophils in two distinct subpopulations, is the glycoprotein CD177. CD177 is expressed on the plasma and granule membranes of 0-100% of circulating neutrophils depending on the donor. Several in vitro studies have linked CD177 to neutrophil transmigration, yet very few have looked at the role of CD177 for tissue recruitment in vivo. We investigate whether the CD177(+)and CD177(-)neutrophil subsets differ in their propensity to migrate to both aseptic- and microbe-triggered inflamed human tissues. Microbe-triggered neutrophil migration was evaluated in samples of gingival crevicular fluid (GCF) from patients with periodontitis, whereas neutrophil migration to aseptic inflammation was evaluated in synovial fluid from patients with inflammatory arthritis, as well as in exudate from experimental skin chambers applied on healthy donors. We found that the proportion of CD177(+)neutrophils was significantly higher in GCF from patients with periodontitis, as compared to blood from the same individuals. Such accumulation of CD177(+)neutrophils was not seen in the two models of aseptic inflammation. Moreover, the proportion of CD177(+)neutrophils in circulation was significantly higher in the periodontitis patient group, as compared to healthy donors. Our data indicate that the CD177(+)neutrophil subset is preferentially recruited to the gingival crevice of periodontitis patients, and may imply that this subtype is of particular importance for situations of microbe-driven inflammation.
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| 5. |
- Davidsson, Marcus, et al.
(author)
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A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism
- 2019
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 116:52, s. 27053-27062
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Journal article (peer-reviewed)abstract
- Adeno-associated virus (AAV) capsid modification enables the generation of recombinant vectors with tailored properties and tropism. Most approaches to date depend on random screening, enrichment, and serendipity. The approach explored here, called BRAVE (barcoded rational AAV vector evolution), enables efficient selection of engineered capsid structures on a large scale using only a single screening round in vivo. The approach stands in contrast to previous methods that require multiple generations of enrichment. With the BRAVE approach, each virus particle displays a peptide, derived from a protein, of known function on the AAV capsid surface, and a unique molecular barcode in the packaged genome. The sequencing of RNA-expressed barcodes from a single-generation in vivo screen allows the mapping of putative binding sequences from hundreds of proteins simultaneously. Using the BRAVE approach and hidden Markov model-based clustering, we present 25 synthetic capsid variants with refined properties, such as retrograde axonal transport in specific subtypes of neurons, as shown for both rodent and human dopaminergic neurons.
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| 6. |
- Davidsson, Per, 1958-, et al.
(author)
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Environmental change, strategic entrepreneurial action, and success : Introduction to a special issue on an important, neglected topic
- 2023
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In: Strategic Entrepreneurship Journal. - : John Wiley & Sons. - 1932-4391 .- 1932-443X. ; 17:2, s. 322-334
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Journal article (other academic/artistic)abstract
- Research Summary: The two premises that underpin this SEJ Special Issue on Environmental Change, Strategic Entrepreneurial Action, and Success are that all environmental changes provide positive potentials for some ventures, and that this has been under-emphasized in past theory and research. After stating these premises and illustrating how present research treats the environment, we proceed to explain how the five articles selected for the special issue advance our thinking in this domain. We then broaden our discussion to how future entrepreneurship research can make further progress by studying interaction among environmental changes as well as their links to entrepreneurial agents, contexts (sectoral, spatial, organizational, etc.) and the entrepreneurial artifact (emerging venture). Throughout, the focus is on the enabling rather than constraining role of environmental changes.Managerial Summary: The COVID-19 pandemic, the digital revolution, and the sustainability transition forced by climate change demonstrate significant business impact of environmental changes, including potentials for new business initiatives. This editorial and the five vanguard articles included in this SEJ Special Issue on Environmental Change, Strategic Entrepreneurial Action, and Success outline how future research can develop better theory and evidence on this important topic. The articles address matters ranging from how COVID-19 facilitated some technology firms' recruiting and reignited media firms' dormant initiatives to how environmental degradations sparked entrepreneurial ecosystem development in Kenya, how the level of environmental dynamism at a venture's birth impact its current ability to benefit from change, and the consequences of passing on potentials provided by environmental change.
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| 7. |
- Etminani, Farzaneh, 1984-, et al.
(author)
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Randomised, siteless study to compare systematic atrial fibrillation screening using enrichment by a risk prediction model with standard care in a Swedish population aged ≥ 65 years : CONSIDERING-AF study design
- 2024
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In: BMJ Open. - London : BMJ Publishing Group Ltd. - 2044-6055. ; 14:1
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia and confers an increased risk of mortality, stroke, heart failure and cognitive decline. There is growing interest in AF screening; however, the most suitable population and device for AF detection remains to be elucidated. Here, we present the design of the CONSIDERING-AF (deteCtiON and Stroke preventIon by moDEl scRreenING for Atrial Fibrillation) study. METHODS AND ANALYSIS: CONSIDERING-AF is a randomised, controlled, siteless, non-blinded diagnostic superiority trial with four parallel groups and a primary endpoint of identifying AF during a 6-month study period set in Region Halland, Sweden. In each group, 740 individuals aged≥65 years will be included. The primary objective is to compare the intervention of AF screening enrichment using a risk prediction model (RPM), followed by 14 days of a continuous ECG patch, with no intervention (standard care). Primary outcome is defined as the incident AF recorded in the Region Halland Information Database after 6 months as compared with standard care. Secondary endpoints include the difference in incident AF between groups enriched or not by the RPM, with and without an invitation to 14 days of continuous ECG recording, and the proportions of oral anticoagulation treatment in the four groups. ETHICS AND DISSEMINATION: This study has ethical approval from the Swedish Ethical Review Authority. Results will be published in peer-reviewed international journals. TRIAL REGISTRATION NUMBER: NCT05838781. © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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| 8. |
- Folkesson Hansson, Sara, 1976, et al.
(author)
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Validation of a prefractionation method followed by two-dimensional electrophoresis - Applied to cerebrospinal fluid proteins from frontotemporal dementia patients.
- 2004
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In: Proteome science. - : Springer Science and Business Media LLC. - 1477-5956. ; 2:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: The aim of this study was firstly, to improve and validate a cerebrospinal fluid (CSF) prefractionation method followed by two-dimensional electrophoresis (2-DE) and secondly, using this strategy to investigate differences between the CSF proteome of frontotemporal dementia (FTD) patients and controls. From each subject three ml of CSF was prefractionated using liquid phase isoelectric focusing prior to 2-DE. RESULTS: With respect to protein recovery and purification potential, ethanol precipitation of the prefractionated CSF sample was found superior, after testing several sample preparation methods.The reproducibility of prefractionated CSF analyzed on 2-D gels was comparable to direct 2-DE analysis of CSF. The protein spots on the prefractionated 2-D gels had an increased intensity, indicating a higher protein concentration, compared to direct 2-D gels. Prefractionated 2-DE analysis of FTD and control CSF showed that 26 protein spots were changed at least two fold. Using mass spectrometry, 13 of these protein spots were identified, including retinol-binding protein, Zn-alpha-2-glycoprotein, proapolipoproteinA1, beta-2-microglobulin, transthyretin, albumin and alloalbumin. CONCLUSION: The results suggest that the prefractionated 2-DE method can be useful for enrichment of CSF proteins and may provide a new tool to investigate the pathology of neurodegenerative diseases. This study confirmed reduced levels of retinol-binding protein and revealed some new biomarker candidates for FTD.
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| 9. |
- Gram, Magnus, et al.
(author)
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Increased levels of hemoglobin and alpha1-microglobulin in Huntington's disease.
- 2012
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In: Frontiers in Bioscience (Elite Edition). - 1945-0508. ; 4, s. 950-957
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Journal article (peer-reviewed)abstract
- Hemoglobin released from damaged erythrocytes is a major pro-oxidant, generator of free radicals and inflammatory mediator. Huntington's disease is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities, in which oxidative stress has been suggested as a possible pathogenic mechanism. In the present work we have investigated levels of hemoglobin and markers of oxidative damage, including the heme- and radical-scavenger alpha1-microglobulin, in plasma and urine samples from two separate sample cohorts, including controls, premanifest gene carriers and subjects at different stages of Huntington's disease. The results show statistically significant increased levels of hemoglobin and alpha1-microglobulin in Huntington's disease urine samples. Interestingly, urine hemoglobin levels correlate with clinical severity. The results suggest that hemolysis may be linked to the pathogenesis of Huntington's disease and that assay of hemoglobin and alpha1-microglobulin may provide biomarkers that are linked to biologically relevant processes.
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| 10. |
- Huber, Maria, et al.
(author)
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Metabolic correlates of dopaminergic loss in dementia with lewy bodies
- 2020
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In: Movement Disorders. - : WILEY. - 0885-3185 .- 1531-8257. ; 35, s. 595-605
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Journal article (peer-reviewed)abstract
- Background Striatal dopamine deficiency and metabolic changes are well-known phenomena in dementia with Lewy bodies and can be quantified in vivo by I-123-Ioflupane brain single-photon emission computed tomography of dopamine transporter and F-18-fluorodesoxyglucose PET. However, the linkage between both biomarkers is ill-understood. Objective We used the hitherto largest study cohort of combined imaging from the European consortium to elucidate the role of both biomarkers in the pathophysiological course of dementia with Lewy bodies. Methods We compared striatal dopamine deficiency and glucose metabolism of 84 dementia with Lewy body patients and comparable healthy controls. After normalization of data, we tested their correlation by region-of-interest-based and voxel-based methods, controlled for study center, age, sex, education, and current cognitive impairment. Metabolic connectivity was analyzed by inter-region coefficients stratified by dopamine deficiency and compared to healthy controls. Results There was an inverse relationship between striatal dopamine availability and relative glucose hypermetabolism, pronounced in the basal ganglia and in limbic regions. With increasing dopamine deficiency, metabolic connectivity showed strong deteriorations in distinct brain regions implicated in disease symptoms, with greatest disruptions in the basal ganglia and limbic system, coincident with the pattern of relative hypermetabolism. Conclusions Relative glucose hypermetabolism and disturbed metabolic connectivity of limbic and basal ganglia circuits are metabolic correlates of dopamine deficiency in dementia with Lewy bodies. Identification of specific metabolic network alterations in patients with early dopamine deficiency may serve as an additional supporting biomarker for timely diagnosis of dementia with Lewy bodies. (c) 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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