| 1. |
- Adler, Jeremy, et al.
(författare)
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Conventional analysis of movement on non-flat surfaces like the plasma membrane makes Brownian motion appear anomalous.
- 2019
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Cells are neither flat nor smooth, which has serious implications for prevailing plasma membrane models and cellular processes like cell signalling, adhesion and molecular clustering. Using probability distributions from diffusion simulations, we demonstrate that 2D and 3D Euclidean distance measurements substantially underestimate diffusion on non-flat surfaces. Intuitively, the shortest within surface distance (SWSD), the geodesic distance, should reduce this problem. The SWSD is accurate for foldable surfaces but, although it outperforms 2D and 3D Euclidean measurements, it still underestimates movement on deformed surfaces. We demonstrate that the reason behind the underestimation is that topographical features themselves can produce both super- and subdiffusion, i.e. the appearance of anomalous diffusion. Differentiating between topography-induced and genuine anomalous diffusion requires characterising the surface by simulating Brownian motion on high-resolution cell surface images and a comparison with the experimental data.
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| 2. |
- Adler, Jeremy, et al.
(författare)
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Membrane topography and the overestimation of protein clustering in single molecule localisation microscopy - identification and correction
- 2024
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Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- According to single-molecule localisation microscopy almost all plasma membrane proteins are clustered. We demonstrate that clusters can arise from variations in membrane topography where the local density of a randomly distributed membrane molecule to a degree matches the variations in the local amount of membrane. Further, we demonstrate that this false clustering can be differentiated from genuine clustering by using a membrane marker to report on local variations in the amount of membrane. In dual colour live cell single molecule localisation microscopy using the membrane probe DiI alongside either the transferrin receptor or the GPI-anchored protein CD59, we found that pair correlation analysis reported both proteins and DiI as being clustered, as did its derivative pair correlation-photoactivation localisation microscopy and nearest neighbour analyses. After converting the localisations into images and using the DiI image to factor out topography variations, no CD59 clusters were visible, suggesting that the clustering reported by the other methods is an artefact. However, the TfR clusters persisted after topography variations were factored out. We demonstrate that membrane topography variations can make membrane molecules appear clustered and present a straightforward remedy suitable as the first step in the cluster analysis pipeline. Variations in membrane topography can lead to the overestimation of protein clustering which can be avoided using a second image of a membrane marker, demonstrated with simulations and live cell SMLM.
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| 3. |
- Agback, Tatiana, et al.
(författare)
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Combined NMR and molecular dynamics conformational filter identifies unambiguously dynamic ensembles of Dengue protease NS2B/NS3pro
- 2023
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Ingår i: COMMUNICATIONS BIOLOGY. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The dengue protease NS2B/NS3pro has been reported to adopt either an 'open' or a 'closed' conformation. We have developed a conformational filter that combines NMR with MD simulations to identify conformational ensembles that dominate in solution. Experimental values derived from relaxation parameters for the backbone and methyl side chains were compared with the corresponding back-calculated relaxation parameters of different conformational ensembles obtained from free MD simulations. Our results demonstrate a high prevalence for the 'closed' conformational ensemble while the 'open' conformation is absent, indicating that the latter conformation is most probably due to crystal contacts. Conversely, conformational ensembles in which the positioning of the co-factor NS2B results in a 'partially' open conformation, previously described in both MD simulations and X-ray studies, were identified by our conformational filter. Altogether, we believe that our approach allows for unambiguous identification of true conformational ensembles, an essential step for reliable drug discovery. A conformational filter that combines NMR with MD simulations to identify conformational ensembles that dominate in solution suggests dengue protease NS2B/NS3pro predominantly exists in a "closed" conformation.
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| 4. |
- Almeida, Jorge, et al.
(författare)
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Neural and behavioral signatures of the multidimensionality of manipulable object processing
- 2023
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Ingår i: COMMUNICATIONS BIOLOGY. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Understanding how we recognize objects requires unravelling the variables that govern the way we think about objects and the neural organization of object representations. A tenable hypothesis is that the organization of object knowledge follows key object-related dimensions. Here, we explored, behaviorally and neurally, the multidimensionality of object processing. We focused on within-domain object information as a proxy for the decisions we typically engage in our daily lives - e.g., identifying a hammer in the context of other tools. We extracted object-related dimensions from subjective human judgments on a set of manipulable objects. We show that the extracted dimensions are cognitively interpretable and relevant - i.e., participants are able to consistently label them, and these dimensions can guide object categorization; and are important for the neural organization of knowledge - i.e., they predict neural signals elicited by manipulable objects. This shows that multidimensionality is a hallmark of the organization of manipulable object knowledge. By obtaining human subjective judgments on a large set of manipulable objects this study provides a set of object-related dimensions and demonstrates that these dimensions are important for the neural and mental representations we hold about objects.
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| 5. |
- Berglund, Fanny, et al.
(författare)
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Evidence for wastewaters as environments where mobile antibiotic resistance genes emerge
- 2023
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- The emergence and spread of mobile antibiotic resistance genes (ARGs) in pathogens have become a serious threat to global health. Still little is known about where ARGs gain mobility in the first place. Here, we aimed to collect evidence indicating where suchinitial mobilizationevents of clinically relevant ARGs may have occurred. We found that the majority of previously identified origin species did not carry the mobilizing elements that likely enabled intracellular mobility of the ARGs, suggesting a necessary interplay between different bacteria. Analyses of a broad range of metagenomes revealed that wastewaters and wastewater-impacted environments had by far the highest abundance of both origin species and corresponding mobilizing elements. Most origin species were only occasionally detected in other environments. Co-occurrence of origin species and corresponding mobilizing elements were rare in human microbiota. Our results identify wastewaters and wastewater-impacted environments as plausible arenas for the initial mobilization of resistance genes.
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| 6. |
- Binder, J., et al.
(författare)
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Machine learning prediction and tau-based screening identifies potential Alzheimer's disease genes relevant to immunity
- 2022
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- With increased research funding for Alzheimer's disease (AD) and related disorders across the globe, large amounts of data are being generated. Several studies employed machine learning methods to understand the ever-growing omics data to enhance early diagnosis, map complex disease networks, or uncover potential drug targets. We describe results based on a Target Central Resource Database protein knowledge graph and evidence paths transformed into vectors by metapath matching. We extracted features between specific genes and diseases, then trained and optimized our model using XGBoost, termed MPxgb(AD). To determine our MPxgb(AD) prediction performance, we examined the top twenty predicted genes through an experimental screening pipeline. Our analysis identified potential AD risk genes: FRRS1, CTRAM, SCGB3A1, FAM92B/CIBAR2, and TMEFF2. FRRS1 and FAM92B are considered dark genes, while CTRAM, SCGB3A1, and TMEFF2 are connected to TREM2-TYROBP, IL-1 beta-TNF alpha, and MTOR-APP AD-risk nodes, suggesting relevance to the pathogenesis of AD. Jessica Binder et al. developed a machine learning model to discover potential drug targets for Alzheimer's disease. They validated their 20 top candidates in several in vitro models, and highlight FRRS1, CTRAM, SCGB3A1, FAM92B/CIBAR2, and TMEFF2 as potential AD risk genes.
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| 7. |
- Blondelle, J., et al.
(författare)
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Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism
- 2019
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 2:178
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Tidskriftsartikel (refereegranskat)abstract
- Biological roles of obscurin and its close homolog Obsl1 (obscurin-like 1) have been enigmatic. While obscurin is highly expressed in striated muscles, Obsl1 is found ubiquitously. Accordingly, obscurin mutations have been linked to myopathies, whereas mutations in Obsl1 result in 3M-growth syndrome. To further study unique and redundant functions of these closely related proteins, we generated and characterized Obsl1 knockouts. Global Obsl1 knockouts are embryonically lethal. In contrast, skeletal muscle-specific Obsl1 knockouts show a benign phenotype similar to obscurin knockouts. Only deletion of both proteins and removal of their functional redundancy revealed their roles for sarcolemmal stability and sarcoplasmic reticulum organization. To gain unbiased insights into changes to the muscle proteome, we analyzed tibialis anterior and soleus muscles by mass spectrometry, uncovering additional changes to the muscle metabolism. Our analyses suggest that all obscurin protein family members play functions for muscle membrane systems.
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| 8. |
- Braeckman, U., et al.
(författare)
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Glacial melt disturbance shifts community metabolism of an Antarctic seafloor ecosystem from net autotrophy to heterotrophy
- 2021
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Climate change-induced glacial melt affects benthic ecosystems along the West Antarctic Peninsula, but current understanding of the effects on benthic primary production and respiration is limited. Here we demonstrate with a series of in situ community metabolism measurements that climate-related glacial melt disturbance shifts benthic communities from net autotrophy to heterotrophy. With little glacial melt disturbance (during cold El Nino spring 2015), clear waters enabled high benthic microalgal production, resulting in net autotrophic benthic communities. In contrast, water column turbidity caused by increased glacial melt run-off (summer 2015 and warm La Nina spring 2016) limited benthic microalgal production and turned the benthic communities net heterotrophic. Ongoing accelerations in glacial melt and run-off may steer shallow Antarctic seafloor ecosystems towards net heterotrophy, altering the metabolic balance of benthic communities and potentially impacting the carbon balance and food webs at the Antarctic seafloor. Ulrike Braeckman et al. use in situ benthic community and benthic biogeochemistry measurements in Potter Cove on the Antarctic Peninsula to show that climate-related glacial melt disturbance shifts benthic communities from net autotrophy to heterotrophy. This study sheds light on how future glacial melt and run-off may affect the metabolic balance of Antarctic benthic communities.
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| 9. |
- Broman, Elias, et al.
(författare)
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Uncovering diversity and metabolic spectrum of animals in dead zone sediments
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Ocean deoxygenation driven by global warming and eutrophication is a primary concern for marine life. Resistant animals may be present in dead zone sediments, however there is lack of information on their diversity and metabolism. Here we combined geochemistry, microscopy, and RNA-seq for estimating taxonomy and functionality of micrometazoans along an oxygen gradient in the largest dead zone in the world. Nematodes are metabolically active at oxygen concentrations below 1.8μmolL−1, and their diversity and community structure are different between low oxygen areas. This is likely due to toxic hydrogen sulfide and its potential to be oxidized by oxygen or nitrate. Zooplankton resting stages dominate the metazoan community, and these populations possibly use cytochrome c oxidase as an oxygen sensor to exit dormancy. Our study sheds light on mechanisms of animal adaptation to extreme environments. These biological resources can be essential for recolonization of dead zones when oxygen conditions improve.
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| 10. |
- Cansby, Emmelie, 1984, et al.
(författare)
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Silencing of STE20-type kinase STK25 in human aortic endothelial and smooth muscle cells is atheroprotective
- 2022
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies highlight the importance of lipotoxic damage in aortic cells as the major pathogenetic contributor to atherosclerotic disease. Since the STE20-type kinase STK25 has been shown to exacerbate ectopic lipid storage and associated cell injury in several metabolic organs, we here investigate its role in the main cell types of vasculature. We depleted STK25 by small interfering RNA in human aortic endothelial and smooth muscle cells exposed to oleic acid and oxidized LDL. In both cell types, the silencing of STK25 reduces lipid accumulation and suppresses activation of inflammatory and fibrotic pathways as well as lowering oxidative and endoplasmic reticulum stress. Notably, in smooth muscle cells, STK25 inactivation hinders the shift from a contractile to a synthetic phenotype. Together, we provide several lines of evidence that antagonizing STK25 signaling in human aortic endothelial and smooth muscle cells is atheroprotective, highlighting this kinase as a new potential therapeutic target for atherosclerotic disease.
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