| 1. |
- Cabrerizo Granados, David, et al.
(författare)
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The clinical phenotype of germline RUNX1 mutations in relation to the accompanying somatic variants and RUNX1 isoform expression
- 2023
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Ingår i: Genes, Chromosomes and Cancer. - : John Wiley & Sons. - 1045-2257 .- 1098-2264. ; 62:11, s. 672-677
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Tidskriftsartikel (refereegranskat)abstract
- Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, abnormal bleeding, and an elevated risk of developing myelodysplastic neoplasia (MDS) and acute myeloid leukemia (AML) at young age. However, it is not known why or how germline carriers of RUNX1 mutations have a particular propensity to develop myeloid hematologic malignancies, but the acquisition and composition of somatic mutations are believed to initiate and determine disease progression. We present a novel family pedigree that shares a common germline RUNX1R204* variant and exhibits a spectrum of somatic mutations and related myeloid malignancies (MM). RUNX1 mutations are associated with inferior clinical outcome; however, the proband of this family developed MDS with ring sideroblasts (MDS-RS), classified as a low-risk MDS subgroup. His relatively indolent clinical course is likely due to a specific somatic mutation in the SF3B1 gene. While the three main RUNX1 isoforms have been ascribed various roles in normal hematopoiesis, they are now being increasingly recognized as involved in myeloid disease. We investigated the RUNX1 transcript isoform patterns in the proband and his sister, who carries the same germline RUNX1R204* variant, and has FPDMM but no MM. We demonstrate a RUNX1a increase in MDS-RS, as previously reported in MM. Interestingly, we identify a striking unbalance of RUNX1b and -c in FPDMM. In conclusion, this report reinforces the relevance of somatic variants on the clinical phenotypic heterogeneity in families with germline RUNX1 deficiency and investigates a potential new role for RUNX1 isoform disequilibrium as a mechanism for development of MM.
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| 2. |
- Delgadillo-Nuno, Erick, et al.
(författare)
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Coastal upwelling systems as dynamic mosaics of bacterioplankton functional specialization
- 2024
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Ingår i: Frontiers in Marine Science. - : Frontiers Media S.A.. - 2296-7745. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Coastal upwelling areas are extraordinarily productive environments where prokaryotic communities, the principal remineralizers of dissolved organic matter (DOM), rapidly respond to phytoplankton bloom and decay dynamics. Nevertheless, the extent of variability of key microbial functions in such dynamic waters remains largely unconstrained. Our metatranscriptomics analyses of 162 marker genes encoding ecologically relevant prokaryotic functions showed distinct spatial-temporal patterns in the NW Iberian Peninsula upwelling area. Short-term (daily) changes in specific bacterial functions associated with changes in biotic and abiotic factors were superimposed on seasonal variability. Taxonomic and functional specialization of prokaryotic communities, based mostly on different resource acquisition strategies, was observed. Our results uncovered the potential influence of prokaryotic functioning on phytoplankton bloom composition and development (e.g., Cellvibrionales and Flavobacteriales increased relative gene expression related to vitamin B12 and siderophore metabolisms during Chaetoceros and Dinophyceae summer blooms). Notably, bacterial adjustments to C- or N-limitation and DMSP availability during summer phytoplankton blooms and different spatial-temporal patterns of variability in the expression of genes with different phosphate affinity indicated a complex role of resource availability in structuring bacterial communities in this upwelling system. Also, a crucial role of Cellvibrionales in the degradation of DOM (carbohydrate metabolism, TCA cycle, proteorhodopsin, ammonium, and phosphate uptake genes) during the summer phytoplankton bloom was found. Overall, this dataset revealed an intertwined mosaic of microbial interactions and nutrient utilization patterns along a spatial-temporal gradient that needs to be considered if we aim to understand the biogeochemical processes in some of the most productive ecosystems in the world ' s oceans.
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| 3. |
- Dossus, Laure, et al.
(författare)
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Reproductive risk factors and endometrial cancer : the European prospective investigation into cancer and nutrition
- 2010
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 127:2, s. 442-451
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial cancer risk has been associated with reproductive factors (age at menarche, age at menopause, parity, age at first and last birth, time since last birth and use of oral contraceptives (OCs)]. However, these factors are closely interrelated and whether they act independently still requires clarification. We conducted a study to examine the association of menstrual and reproductive variables with the risk of endometrial cancer among the European Prospective Investigation into Cancer and Nutrition (EPIC). Among the 302,618 women eligible for the study, 1,017 incident endometrial cancer cases were identified. A reduction in endometrial cancer risk was observed in women with late menarche, early menopause, past OC use, high parity and a shorter time since last full-term pregnancy (FTP). No association was observed for duration of breast feeding after adjustment for number of FTP or for abortion (spontaneous or induced). After mutual adjustment, late age at menarche, early age at menopause and duration of OC use showed similar risk reductions of 7-8% per year of menstrual life, whereas the decreased risk associated with cumulative duration of FTPs was stronger (22% per year). In conclusion, our findings confirmed a reduction in risk of endometrial cancer with factors associated with a lower cumulative exposure to estrogen and/or higher exposure to progesterone, such as increasing number of FTPs and shorter menstrual lifespan and, therefore, support an important role of hormonal mechanisms in endometrial carcinogenesis.
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| 4. |
- Herland, Anna, et al.
(författare)
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Electrochemical Control of Growth Factor Presentation To Steer Neural Stem Cell Differentiation
- 2011
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Ingår i: Angewandte Chemie International Edition. - Weinheim : Wiley-VCH Verlagsgesellschaft. - 1433-7851 .- 1521-3773. ; 50:52, s. 12529-12533
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Tidskriftsartikel (refereegranskat)abstract
- Graphical Abstract Let it grow: The conjugated polymer poly(3,4-ethylenedioxythiophene) (PEDOT) was synthesized with heparin as the counterion to form a cell culture substrate. The surface of PEDOT:heparin in the neutral state associated biologically active growth factors (see picture). Electrochemical in situ oxidation of PEDOT during live cell culture decreased the bioavailability of the growth factor and created an exact onset of neural stem cell differentiation.
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| 5. |
- Jager, Edwin, 1973-, et al.
(författare)
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Mechanotransduction in cells using polypyrrole microactuators
- 2011
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Ingår i: EuroEAP 2011 - First International conference on Electromechanically Active Polymer (EAP) transducers & artificial muscles.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The effect of mechanical forces on cells is a relatively unexplored area of cell biology. However, mechanical forces play an important role in cell proliferation, function, and stem cell differentiation. For instance in muscle contraction, bone growth, and morphogenesis. There is only a limited selection of tools to study this on a single cell level and/or follow the events in real time. Here, we present novel tools in order to mechanically stimulate (stem) cells both on a single cell level as well as parts of functional monolayers. The devices are designed in order to function with different imaging techniques commonly used in cell biology. The mechanical stimulus is provided by polypyrrole microactuators. These actuators can be operated in salt solutions including cell culture media, making them well suited for cell biology applications. In addition, polypyrrole is known to be biocompatible. We will present devices with which we can stretch cells and show the cellular response to this mechanical stimulation. Since the dawn of eukaryotic cells many parallel molecular mechanisms that respond to mechanical stimuli have evolved. This technology allows us to begin the investigation of these mechanisms on a single cell level.
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| 6. |
- Joglar, Vanessa, et al.
(författare)
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Cobalamin and microbial plankton dynamics along a coastal to offshore transect in the Eastern North Atlantic Ocean
- 2021
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Ingår i: Environmental Microbiology. - : John Wiley & Sons. - 1462-2912 .- 1462-2920. ; 23:3, s. 1559-1583
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Tidskriftsartikel (refereegranskat)abstract
- Cobalamin (B12) is an essential cofactor that is exclusively synthesized by some prokaryotes while many prokaryotes and eukaryotes require an external supply of B12. The spatial and temporal availability of B12 is poorly understood in marine ecosystems. Field measurements of B12 along with a large set of ancillary biotic and abiotic factors were obtained during three oceanographic cruises in the NW Iberian Peninsula, covering different spatial and temporal scales. B12 concentrations were remarkably low (<1.5 pM) in all samples, being significantly higher at the subsurface Eastern North Atlantic Central Water than at shallower depths, suggesting that B12 supply in this water mass is greater than demand. Multiple regression models excluded B12 concentration as predictive variable for phytoplankton biomass or production, regardless of the presence of B12-requiring algae. Prokaryote production was the best predictor for primary production, and eukaryote community composition was better correlated with prokaryote community composition than with nutritional resources, suggesting that biotic interactions play a significant role in regulating microbial communities. Interestingly, co-occurrence network analyses based on 16S and 18S rRNA sequences allowed the identification of significant associations between potential B12 producers and consumers (e.g. Thaumarchaeota and Dynophyceae, or Amylibacter and Ostreococcus respectively), which can now be investigated using model systems in the laboratory.
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| 7. |
- Joglar, Vanessa, et al.
(författare)
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Microbial Plankton Community Structure and Function Responses to Vitamin B-12 and B-1 Amendments in an Upwelling System
- 2021
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Ingår i: Applied and Environmental Microbiology. - : American Society for Microbiology. - 0099-2240 .- 1098-5336. ; 87:22
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Tidskriftsartikel (refereegranskat)abstract
- B vitamins are essential cofactors for practically all living organisms on Earth and are produced by a selection of microorganisms. An imbalance between high demand and limited production, in concert with abiotic processes, may explain the low availability of these vitamins in marine systems. Natural microbial communities from surface shelf water in the productive area off northwestern Spain were enclosed in mesocosms in winter, spring, and summer 2016. In order to explore the impact of B-vitamin availability on microbial community composition (16S and 18S rRNA gene sequence analysis) and bacterial function (metatranscriptomics analysis) in different seasons, enrichment experiments were conducted with seawater from the mesocosms. Our findings revealed that significant increases in phytoplankton or prokaryote biomass associated with vitamin B-12 and/or B-1 amendments were not accompanied by significant changes in community composition, suggesting that most of the microbial taxa benefited from the external B-vitamin supply. Metatranscriptome analysis suggested that many bacteria were potential consumers of vitamins B-12 and B-1, although the relative abundance of reads related to synthesis was ca. 3.6-fold higher than that related to uptake. Alteromonadales and Oceanospirillales accounted for important portions of vitamin B-1 and B-12 synthesis gene transcription, despite accounting for only minor portions of the bacterial community. Flavobacteriales appeared to be involved mostly in vitamin B-12 and B-1 uptake, and Pelagibacterales expressed genes involved in vitamin B-1 uptake. Interestingly, the relative expression of vitamin B-12 and B-1 synthesis genes among bacteria strongly increased upon inorganic nutrient amendment. Collectively, these findings suggest that upwelling events intermittently occurring during spring and summer in productive ecosystems may ensure an adequate production of these cofactors to sustain high levels of phytoplankton growth and biomass. IMPORTANCE B vitamins are essential growth factors for practically all living organisms on Earth that are produced by a selection of microorganisms. An imbalance between high demand and limited production may explain the low concentration of these compounds in marine systems. In order to explore the impact of B-vitamin availability on bacteria and algae in the coastal waters off northwestern Spain, six experiments were conducted with natural surface water enclosed in winter, spring, and summer. Our findings revealed that increases in phytoplankton or bacterial growth associated with B-12 and/or B-1 amendments were not accompanied by significant changes in community composition, suggesting that most microorganisms benefited from the B-vitamin supply. Our analyses confirmed the role of many bacteria as consumers of vitamins B-12 and B-1, although the relative abundance of genes related to synthesis was ca. 3.6-fold higher than that related to uptake. Interestingly, prokaryote expression of B-12 and B-1 synthesis genes strongly increased when inorganic nutrients were added. Collectively, these findings suggest that upwelling of cold and nutrient-rich waters occurring during spring and summer in this coastal area may ensure an adequate production of B vitamins to sustain high levels of algae growth and biomass.
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| 8. |
- Jungebluth, Philipp, et al.
(författare)
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Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite : a proof-of-concept study
- 2011
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 378:9808, s. 1997-2004
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Tidskriftsartikel (refereegranskat)abstract
- Background Tracheal tumours can be surgically resected but most are an inoperable size at the time of diagnosis; therefore, new therapeutic options are needed. We report the clinical transplantation of the tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite. Methods A 36-year-old male patient, previously treated with debulking surgery and radiation therapy, presented with recurrent primary cancer of the distal trachea and main bronchi. After complete tumour resection, the airway was replaced with a tailored bioartificial nanocomposite previously seeded with autologous bone-marrow mononuclear cells via a bioreactor for 36 h. Postoperative granulocyte colony-stimulating factor filgrastim (10 mu g/kg) and epoetin beta (40 000 UI) were given over 14 days. We undertook flow cytometry, scanning electron microscopy, confocal microscopy epigenetics, multiplex, miRNA, and gene expression analyses. Findings We noted an extracellular matrix-like coating and proliferating cells including a CD105+ subpopulation in the scaffold after the reseeding and bioreactor process. There were no major complications, and the patient was asymptomatic and tumour free 5 months after trans plantation. The bioartificial nanocomposite has patent anastomoses, lined with a vascularised neomucosa, and was partly covered by nearly healthy epithelium. Post-operatively, we detected a mobilisation of peripheral cells displaying increased mesenchymal stromal cell phenotype, and upregulation of epoetin receptors, antiapoptotic genes, and miR-34 and miR-449 biomarkers. These findings, together with increased levels of regenerative-associated plasma factors, strongly suggest stem-cell homing and cell-mediated wound repair, extracellular matrix remodelling, and neovascularisation of the graft. Interpretation Tailor-made bioartificial scaffolds can be used to replace complex airway defects. The bioreactor reseeding process and pharmacological-induced site-specific and graft-specific regeneration and tissue protection are key factors for successful clinical outcome.
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| 9. |
- Lundin, Vanessa
(författare)
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Biophysical regulation of cell function : the yin and yang of the microenvironment
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- From embryonic development to tissue regeneration and disease progression, the human body is continuously subject to mechanical stresses. Physical forces are increasingly recognized as major microenvironmental cues that control tensional homeostasis in tissues. Cells constantly receive and translate physical cues into biological messages, which in turn dictate cell shape, state and function. While much is known about biochemical signaling, many of the mechanisms that drive cell outcome in response to biophysical influences remain to be uncovered. Here we have investigated biophysical regulation of cell function. The goal was to gain a deeper understanding of fundamental principles that govern cell behavior in response to physical stimuli. To carefully recapitulate signaling in the in vivo microenvironment, we utilized a battery of tools that stem from the field of bioengineering. We used conjugated polymers to develop a novel neural stem cell culture substrate with anchored growth factors to promote cell self-renewal. Upon an electrochemical switch, growth factor presentation was reversed, which initiated cellular differentiation along the neuronal lineages. This electroactive material allowed for temporal control of growth factor presentation, increased growth factor stability and a closer reflection of biological signaling during brain development in vivo. In addition to temporal changes in growth factor presentation, mechanical stiffness of tissues is also dynamically altered over time. Cells sense and respond to the mechanics of their substrate - be it the extracellular matrix, neighboring cells or artificial matrix in cell culture. Using biologically relevant elastic substrates to study cell function in vitro has proven beneficial, as the in vivo microenvironment usually is much softer than rigid plastic dishes. Stiffened tumor stroma is a hallmark of cancer and understanding mechanosensitive pathways involved in the onset of cancer is key in identifying strategies for cancer treatment. We have therefore investigated the role of matrix stiffness in Notch signaling in breast cancer cells. This signaling pathway is a highly conserved cell-to-cell communication system that regulates cell fate in development and disease. Aberrant Notch signaling in breast cancer has been found to correlate with invasion and patient outcome. Our results show that we can tune cell stiffness and migration by regulating Notch activity and matrix stiffness. We propose an opportunity to target the cancer cell/microenvironment interface instead of the Notch pathway itself in the development of cancer therapies. Finally, we have studied the role of nanoarchitecture of ephrin ligands in Eph receptor activation. Eph/ephrin signaling is a cell-to-cell communication pathway, which regulates cell migration and proliferation. Dysregulation of this pathway has been associated with a multitude of human diseases, including breast cancer. Here, we developed a new tool based on DNA origami, which allows for precise positioning of ephrin ligands on DNA at the nanoscale. We found that Eph receptor activation and downstream events are regulated by ephrin spatial distribution. This work contributes to our understanding of how physical cues in the form of ligand presentation impact breast cancer cell behavior. Ultimately, elucidating the mechanisms involved in biophysical regulation of cell function is necessary to understand cellular dysfunction and diseases.
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| 10. |
- Lundin, Vanessa, et al.
(författare)
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Control of Neural Stem Cell Survival by Electroactive Polymer Substrates
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4, s. 0018624-
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Tidskriftsartikel (refereegranskat)abstract
- Stem cell function is regulated by intrinsic as well as microenvironmental factors, including chemical and mechanical signals. Conducting polymer-based cell culture substrates provide a powerful tool to control both chemical and physical stimuli sensed by stem cells. Here we show that polypyrrole (PPy), a commonly used conducting polymer, can be tailored to modulate survival and maintenance of rat fetal neural stem cells (NSCs). NSCs cultured on PPy substrates containing different counter ions, dodecylbenzenesulfonate (DBS), tosylate (TsO), perchlorate (ClO4) and chloride (Cl), showed a distinct correlation between PPy counter ion and cell viability. Specifically, NSC viability was high on PPy(DBS) but low on PPy containing TsO, ClO4 and Cl. On PPy(DBS), NSC proliferation and differentiation was comparable to standard NSC culture on tissue culture polystyrene. Electrical reduction of PPy(DBS) created a switch for neural stem cell viability, with widespread cell death upon polymer reduction. Coating the PPy(DBS) films with a gel layer composed of a basement membrane matrix efficiently prevented loss of cell viability upon polymer reduction. Here we have defined conditions for the biocompatibility of PPy substrates with NSC culture, critical for the development of devices based on conducting polymers interfacing with NSCs.
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| 11. |
- Pontiller, Benjamin, MSc, 1985-, et al.
(författare)
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Rapid bacterioplankton transcription cascades regulate organic matter utilization during phytoplankton bloom progression in a coastal upwelling system
- 2022
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Ingår i: The ISME Journal. - : Nature Publishing Group. - 1751-7362 .- 1751-7370. ; 16, s. 2360-2372
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Tidskriftsartikel (refereegranskat)abstract
- Coastal upwelling zones are veritable hotspots of oceanic productivity, driven by phytoplankton photosynthesis. Bacteria, in turn, grow on and are the principal remineralizers of dissolved organic matter (DOM) produced in aquatic ecosystems. However, knowledge of the molecular processes that key bacterial taxa employ to regulate the turnover of phytoplankton-derived DOM has yet to advance. We therefore carried out a comparative metatranscriptomics analysis with parallel sampling of bacterioplankton during experimental and natural phytoplankton blooms in the Northwest Iberian upwelling system. The experiment analysis uncovered a taxon-specific progression of transcriptional responses from bloom development, over early decay, to senescence phases. This included pronounced order-specific differences in regulation of glycoside hydrolases and peptidases along with transporters, supporting the notion that functional resource partitioning is dynamically structured by temporal changes in available DOM. In addition, comparative analysis of experiment and field blooms revealed a large degree of metabolic plasticity in the degradation and uptake of carbohydrates and nitrogen-rich compounds, suggesting these gene systems critically contribute to modulating the stoichiometry of the coastal DOM pool. Collectively, our findings suggest that cascades of transcriptional responses in gene systems for the utilization of organic matter and nutrients largely shape the fate of organic matter on the short time scales typical of upwelling-driven phytoplankton blooms.
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| 12. |
- Shaw, Alan, et al.
(författare)
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Spatial control of membrane receptor function using ligand nanocalipers
- 2014
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Ingår i: Nature Methods. - : Springer Nature. - 1548-7091 .- 1548-7105. ; 11:8, s. 841-846
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Tidskriftsartikel (refereegranskat)abstract
- The spatial organization of membrane-bound ligands is thought to regulate receptor-mediated signaling. However, direct regulation of receptor function by nanoscale distribution of ligands has not yet been demonstrated, to our knowledge. We developed rationally designed DNA origami nanostructures modified with ligands at well-defined positions. Using these 'nanocalipers' to present ephrin ligands, we showed that the nanoscale spacing of ephrin-A5 directs the levels of EphA2 receptor activation in human breast cancer cells. Furthermore, we found that the nanoscale distribution of ephrin-A5 regulates the invasive properties of breast cancer cells. Our ligand nanocaliper approach has the potential to provide insight into the roles of ligand nanoscale spatial distribution in membrane receptor mediated signaling.
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