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Yabrag, A., Ullah, N., Baryalai, P., Ahmad, I., Zlatkov, N., Toh, E., . . . Nadeem, A. (2025). A new understanding of Acanthamoeba castellanii: dispelling the role of bacterial pore-forming toxins in cyst formation and amoebicidal actions. Cell Death Discovery, 11(1), Article ID 66.
Open this publication in new window or tab >>A new understanding of Acanthamoeba castellanii: dispelling the role of bacterial pore-forming toxins in cyst formation and amoebicidal actions
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2025 (English)In: Cell Death Discovery, E-ISSN 2058-7716, Vol. 11, no 1, article id 66Article in journal (Refereed) Published
Abstract [en]

Pore-forming toxins (PFTs) are recognized as major virulence factors produced by both Gram-positive and Gram-negative bacteria. While the effects of PFTs have been extensively investigated using mammalian cells as a model system, their interactions with the environmental host, Acanthamoeba castellanii remains less understood. This study employed high-throughput image screening (HTI), advanced microscopy, western blot analysis, and cytotoxicity assays to evaluate the impact of PFT-producing bacterial species on their virulence against A. castellanii. Our unbiased HTI data analysis reveals that the cyst induction of A. castellanii in response to various bacterial species does not correlate with the presence of PFT-producing bacteria. Moreover, A. castellanii demonstrates resistance to PFT-mediated cytotoxicity, in contrast to mammalian macrophages. Notably, Vibrio anguillarum and Ralstonia eutropha triggered a high frequency of cyst formation and cytotoxicity in infected A. castellanii. In summary, our findings reveal that A. castellanii exhibits a unique resistance to PFTs, unlike mammalian cells, suggesting its potential ecological role as a reservoir for diverse pathogenic species and its influence on their persistence and proliferation in the environment. (Figure presented.)

Place, publisher, year, edition, pages
Springer Nature, 2025
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-236464 (URN)10.1038/s41420-025-02345-8 (DOI)001425908200001 ()39971918 (PubMedID)2-s2.0-85219721640 (Scopus ID)
Available from: 2025-03-19 Created: 2025-03-19 Last updated: 2025-03-19Bibliographically approved
Li, X., Mu, L., Peng, H., Wai, S. N., Pu, L. & Dong, B. (2025). Development of cell labeling and gene editing tools in urochordate Ciona. Marine Life Science and Technology, Article ID e3002762.
Open this publication in new window or tab >>Development of cell labeling and gene editing tools in urochordate Ciona
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2025 (English)In: Marine Life Science and Technology, ISSN 2096-6490, article id e3002762Article in journal (Refereed) Epub ahead of print
Abstract [en]

Urochordate Ciona spp. are ideal marine model organisms for studying embryogenesis and developmental and evolutionary biology. However, the effective implementation of genetic labeling and CRISPR/Cas9-based editing tools at cellular resolution remains challenging. This study successfully developed and validated a collection of Gateway-based vectors for cell labeling in Ciona spp. The destination vector sets contained two Gateway cassettes flanked by Minos sites, allowing the N- or C-terminal tagging of a protein of interest with various fluorescent markers. In addition, we optimized the CRISPR/Cas9 and CRISPR/dCas9 systems by incorporating P2A-mCherry, a fluorescent indicator for Cas9 expression at cellular resolution. We demonstrated the effective destruction or inhibition of target genes when CRISPR constructs were introduced into fertilized eggs. Furthermore, we engineered a dual fluorescence sensor system that helps visualize successful gene knockouts at the cellular level in specific tissues. The genetic tools developed in this study offer a robust method for gene expression, cell tracking, and subcellular protein localization while also facilitating tissue-specific functional analysis in Ciona embryos and other model systems.

Place, publisher, year, edition, pages
Springer Nature, 2025
Keywords
Cell labeling, Ciona, CRISPR/Cas9, Fluorescent sensor, Gateway
National Category
Biochemistry Molecular Biology
Identifiers
urn:nbn:se:umu:diva-240950 (URN)10.1007/s42995-025-00300-1 (DOI)001501042000001 ()2-s2.0-105007090738 (Scopus ID)
Available from: 2025-07-01 Created: 2025-07-01 Last updated: 2025-07-01
Baryalai, P., Irenaeus, D., Toh, E., Ramstedt, M., Uhlin, B. E., Nadeem, A. & Wai, S. N. (2025). Hemagglutinin protease hapa associated with vibrio cholerae outer membrane vesicles (OMVs) disrupts tight and adherens junctions. Journal of Extracellular Vesicles, 14(5), Article ID e70092.
Open this publication in new window or tab >>Hemagglutinin protease hapa associated with vibrio cholerae outer membrane vesicles (OMVs) disrupts tight and adherens junctions
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2025 (English)In: Journal of Extracellular Vesicles, E-ISSN 2001-3078, Vol. 14, no 5, article id e70092Article in journal (Refereed) Published
Abstract [en]

This study explores the virulence mechanisms of Vibrio cholerae, with a particular emphasis on HapA, a zinc metalloprotease delivered via outer membrane vesicles (OMVs). The findings reveal that OMV-associated HapA disrupts the integrity of tight and adherens junctions in intestinal epithelial cell models more effectively than its purified counterpart, suggesting that association with OMVs substantially potentiates the pathogenic effects of HapA. The study further details the uptake of V. cholerae OMVs by epithelial cells, as well as their targeted degradation of key junctional proteins, including claudin, ZO-1, and ?-catenin. These results highlight the critical role of OMV-associated HapA in compromising epithelial barrier function. Additionally, the use of spheroids and intestinal organoids in our experiments provides deeper insight into bacterial pathogenesis, offering valuable information for the development of targeted therapeutic strategies.

Place, publisher, year, edition, pages
John Wiley & Sons, 2025
Keywords
adherens junctions, cholera, outer membrane vesicles, protease, tight junctions, virulence
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-241753 (URN)10.1002/jev2.70092 (DOI)001494292700001 ()40415227 (PubMedID)2-s2.0-105006502317 (Scopus ID)
Funder
Swedish Research Council, 18-02914Swedish Research Council, 2022-00981Swedish Research Council, 2019-01720Swedish Cancer Society, 2020-711Swedish Cancer Society, 2023-2821The Kempe Foundations, SMK21-0024
Available from: 2025-06-30 Created: 2025-06-30 Last updated: 2025-07-01Bibliographically approved
Pu, L., Wang, J., Nilsson, L., Zhao, L., Williams, C., Chi, G., . . . Chen, C. (2025). Shaker/Kv1 potassium channel SHK-1 protects against pathogen infection and oxidative stress in C. elegans. PLOS Genetics, 21(2), Article ID e1011554.
Open this publication in new window or tab >>Shaker/Kv1 potassium channel SHK-1 protects against pathogen infection and oxidative stress in C. elegans
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2025 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 21, no 2, article id e1011554Article in journal (Refereed) Published
Abstract [en]

The Shaker/Kv1 subfamily of voltage-gated potassium (K+) channels is essential for modulating membrane excitability. Their loss results in prolonged depolarization and excessive calcium influx. These channels have also been implicated in a variety of other cellular processes, but the underlying mechanisms remain poorly understood. Through comprehensive screening of K+ channel mutants in C. elegans, we discovered that shk-1 mutants are highly susceptible to bacterial pathogen infection and oxidative stress. This vulnerability is associated with reduced glycogen levels and substantial mitochondrial dysfunction, including decreased ATP production and dysregulated mitochondrial membrane potential under stress conditions. SHK-1 is predominantly expressed and functions in body wall muscle to maintain glycogen storage and mitochondrial homeostasis. RNA-sequencing data reveal that shk-1 mutants have decreased expression of a set of cation-transporting ATPases (CATP), which are crucial for maintaining electrochemical gradients. Intriguingly, overexpressing catp-3, but not other catp genes, restores the depolarization of mitochondrial membrane potential under stress and enhances stress tolerance in shk-1 mutants. This finding suggests that increased catp-3 levels may help restore electrochemical gradients disrupted by shk-1 deficiency, thereby rescuing the phenotypes observed in shk-1 mutants. Overall, our findings highlight a critical role for SHK-1 in maintaining stress tolerance by regulating glycogen storage, mitochondrial homeostasis, and gene expression. They also provide insights into how Shaker/Kv1 channels participate in a broad range of cellular processes.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2025
National Category
Molecular Biology Infectious Medicine Cell Biology
Identifiers
urn:nbn:se:umu:diva-235380 (URN)10.1371/journal.pgen.1011554 (DOI)001415949000001 ()39913540 (PubMedID)2-s2.0-85217033990 (Scopus ID)
Funder
Swedish Research Council, 2021-06602Swedish Research Council, 2022-06725Swedish Research Council, 2024-00409Swedish Research Council, 2022- 00981Swedish Research Council, 2018-02216Swedish Research Council, 2024-04141Swedish Cancer Society, 23 3102 PjSwedish Cancer Society, 2023-2821The Kempe Foundations, SMK21-0024The Kempe Foundations, JCSMK24-0012EU, European Research Council, 802653 OXYGEN SENSING
Available from: 2025-02-24 Created: 2025-02-24 Last updated: 2025-05-09Bibliographically approved
Oscarsson, J., Bao, K., Shiratsuchi, A., Grossmann, J., Wolski, W., Aung, K. M., . . . Bostanci, N. (2024). Bacterial symbionts in oral niche use type VI secretion nanomachinery for fitness increase against pathobionts. iScience, Article ID 109650.
Open this publication in new window or tab >>Bacterial symbionts in oral niche use type VI secretion nanomachinery for fitness increase against pathobionts
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2024 (English)In: iScience, ISSN 2589-0042, article id 109650Article in journal (Refereed) Published
Abstract [en]

Microbial ecosystems experience spatial and nutrient restrictions, leading to the coevolution of cooperation and competition among cohabiting species. To increase their fitness for survival, bacteria exploit machinery to antagonizing rival species upon close contact. As such, the bacterial type VI secretion system (T6SS) nanomachinery, typically expressed by pathobionts, can transport proteins directly into eukaryotic or prokaryotic cells, consequently killing cohabiting competitors. Here we demonstrate first time that oral symbiont Aggregatibacter aphrophilus possesses a T6SS and can eliminate its close relative oral pathobiont Aggregatibacter actinomycetemcomitans using its T6SS. These findings bring newer the anti-bacterial prospects of symbionts against cohabiting pathobionts while introducing presence of an active T6SS in the oral cavity.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Pathobiont, aggregatibacter species, Type VI secretion system
National Category
Infectious Medicine Dentistry
Research subject
Microbiology
Identifiers
urn:nbn:se:umu:diva-223048 (URN)10.1016/j.isci.2024.109650 (DOI)001229209500001 ()2-s2.0-85190136052 (Scopus ID)
Funder
Swedish Research Council, 2022-010
Available from: 2024-04-09 Created: 2024-04-09 Last updated: 2025-04-24Bibliographically approved
Mushtaq, F., Nadeem, A., Yabrag, A., Bala, A., Karah, N., Zlatkov, N., . . . Ahmad, I. (2024). Colony phase variation switch modulates antimicrobial tolerance and biofilm formation in Acinetobacter baumannii. Microbiology Spectrum, 12(2), Article ID e02956-23.
Open this publication in new window or tab >>Colony phase variation switch modulates antimicrobial tolerance and biofilm formation in Acinetobacter baumannii
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2024 (English)In: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 12, no 2, article id e02956-23Article in journal (Refereed) Published
Abstract [en]

Carbapenem-resistant Acinetobacter baumannii causes one of the most difficult-to-treat nosocomial infections. Polycationic drugs like polymyxin B or colistin and tetracycline drugs such as doxycycline or minocycline are commonly used to treat infections caused by carbapenem-resistant A. baumannii. Here, we show that a subpopulation of cells associated with the opaque/translucent colony phase variation by A. baumannii AB5075 displays differential tolerance to subinhibitory concentrations of colistin and tetracycline. Using a variety of microscopic techniques, we demonstrate that extracellular polysaccharide moieties mediate colistin tolerance to opaque A. baumannii at single-cell level and that mushroom-shaped biofilm structures protect opaque bacteria at the community level. The colony switch phenotype is found to alter several traits of A. baumannii, including long-term survival under desiccation, tolerance to ethanol, competition with Escherichia coli, and intracellular survival in the environmental model host Acanthamoeba castellanii. Additionally, our findings suggest that extracellular DNA associated with membrane vesicles can promote colony switching in a DNA recombinase-dependent manner.

Importance: As a WHO top-priority drug-resistant microbe, Acinetobacter baumannii significantly contributes to hospital-associated infections worldwide. One particularly intriguing aspect is its ability to reversibly switch its colony morphotype on agar plates, which has been remarkably underexplored. In this study, we employed various microscopic techniques and phenotypic assays to investigate the colony phase variation switch under different clinically and environmentally relevant conditions. Our findings reveal that the presence of a poly N-acetylglucosamine-positive extracellular matrix layer contributes to the protection of bacteria from the bactericidal effects of colistin. Furthermore, we provide intriguing insights into the multicellular lifestyle of A. baumannii, specifically in the context of colony switch variation within its predatory host, Acanthamoeba castellanii.

Place, publisher, year, edition, pages
American Society for Microbiology, 2024
Keywords
colisitin, opaque colony, translucent colony
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-221121 (URN)10.1128/spectrum.02956-23 (DOI)001141161500001 ()38205963 (PubMedID)2-s2.0-85184519514 (Scopus ID)
Funder
Swedish Research Council, 2020-06136Swedish Research Council, 2019-01720Swedish Research Council, 2018-02914Swedish Research Council, 2016-00968Swedish Research Council, 2019-00217The Kempe Foundations, SMK-1961The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IB2022-9222Swedish Cancer Society, 2017-419
Available from: 2024-02-20 Created: 2024-02-20 Last updated: 2024-02-20Bibliographically approved
Bodra, N., Toh, E., Nadeem, A., Wai, S. N. & Persson, K. (2024). MakC and MakD are two proteins associated with a tripartite toxin of Vibrio cholerae. Frontiers in Microbiology, 15, Article ID 1457850.
Open this publication in new window or tab >>MakC and MakD are two proteins associated with a tripartite toxin of Vibrio cholerae
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2024 (English)In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 15, article id 1457850Article in journal (Refereed) Published
Abstract [en]

Pathogenic serotypes of Vibrio cholerae, transmitted through contaminated water and food, are responsible for outbreaks of cholera, an acute diarrheal disease. While the cholera toxin is the primary virulence factor, V. cholerae also expresses other virulence factors, such as the tripartite toxin MakABE that is secreted via the bacterial flagellum. These three proteins are co-expressed with two accessory proteins, MakC and MakD, whose functions remain unknown. Here, we present the crystal structures of MakC and MakD, revealing that they are similar in both sequence and structure but lack other close structural relatives. Our study further investigates the roles of MakC and MakD, focusing on their impact on the expression and secretion of the components of the MakABE tripartite toxin. Through deletion mutant analysis, we found that individual deletions of makC or makD do not significantly affect MakA expression or secretion. However, the deletion of both makC and makD impairs the expression of MakB, which is directly downstream, and decreases the expression of MakE, which is separated from makCD by two genes. Conversely, MakA, encoded by the makA gene located between makB and makE, is expressed normally but its secretion is impaired. Additionally, our findings indicate that MakC, in contrast to MakD, exhibits strong interactions with other proteins. Furthermore, both MakC and MakD were observed to be localized within the cytosol of the bacterial cell. This study provides new insights into the regulatory mechanisms affecting the Mak protein family in V. cholerae and highlights the complex interplay between gene proximity and protein expression.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2024
Keywords
crystal structure, liposome, secretion, toxin, Vibrio cholerae
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-231329 (URN)10.3389/fmicb.2024.1457850 (DOI)001334880400001 ()39421563 (PubMedID)2-s2.0-85206980493 (Scopus ID)
Funder
The Kempe Foundations, JCSMK22-0138The Kempe Foundations, SMK-1969.3Swedish Research Council, 2016-05009Swedish Research Council, 2022-00981Swedish Research Council, 2022-04779Swedish Cancer Society, 2023-2821
Available from: 2024-10-31 Created: 2024-10-31 Last updated: 2024-10-31Bibliographically approved
Löwenmark, T., Köhn, L., Kellgren, T., Rosenbaum, W., Bronnec, V., Löfgren Burström, A., . . . Palmqvist, R. (2024). Parvimonas micra forms a distinct bacterial network with oral pathobionts in colorectal cancer patients. Journal of Translational Medicine, 22(1), Article ID 947.
Open this publication in new window or tab >>Parvimonas micra forms a distinct bacterial network with oral pathobionts in colorectal cancer patients
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2024 (English)In: Journal of Translational Medicine, E-ISSN 1479-5876, Vol. 22, no 1, article id 947Article in journal (Refereed) Published
Abstract [en]

Background: Mounting evidence suggests a significant role of the gut microbiota in the development and progression of colorectal cancer (CRC). In particular, an over-representation of oral pathogens has been linked to CRC. The aim of this study was to further investigate the faecal microbial landscape of CRC patients, with a focus on the oral pathogens Parvimonas micra and Fusobacterium nucleatum.

Methods: In this study, 16S rRNA sequencing was conducted using faecal samples from CRC patients (n = 275) and controls without pathological findings (n = 95).

Results: We discovered a significant difference in microbial composition depending on tumour location and microsatellite instability (MSI) status, with P. micra, F. nucleatum, and Peptostreptococcus stomatis found to be more abundant in patients with MSI tumours. Moreover, P. micra and F. nucleatum were associated with a cluster of CRC-related bacteria including Bacteroides fragilis as well as with other oral pathogens such as P. stomatis and various Porphyromonas species. This cluster was distinctly different in the control group, suggesting its potential linkage with CRC.

Conclusions: Our results suggest a similar distribution of several CRC-associated bacteria within CRC patients, underscoring the importance of considering the concomitant presence of bacterial species in studies investigating the mechanisms of CRC development and progression.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Colorectal cancer, Fusobacterium nucelatum, Intestinal microbiota, Oral pathobionts, Parvimonas micra
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-231532 (URN)10.1186/s12967-024-05720-8 (DOI)001338945800003 ()39420333 (PubMedID)2-s2.0-85206620492 (Scopus ID)
Funder
Swedish Cancer SocietySjöberg FoundationSwedish Research CouncilCancerforskningsfonden i NorrlandUmeå UniversityRegion Västerbotten
Available from: 2024-11-21 Created: 2024-11-21 Last updated: 2025-02-24Bibliographically approved
Verma, A., Amnebrink, D., Lee, C. C., Wai, S. N., Sandblad, L., Pinhassi, J. & Wikner, J. (2024). Prokaryotic morphological features and maintenance activities governed by seasonal productivity conditions. FEMS Microbiology Ecology, 100(11), Article ID fiae121.
Open this publication in new window or tab >>Prokaryotic morphological features and maintenance activities governed by seasonal productivity conditions
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2024 (English)In: FEMS Microbiology Ecology, ISSN 0168-6496, E-ISSN 1574-6941, Vol. 100, no 11, article id fiae121Article in journal (Refereed) Published
Abstract [en]

Prokaryotic maintenance respiration and associated metabolic activities constitute a considerable proportion of the total respiration of carbon to CO2 in the ocean's mixed layer. However, seasonal influences on prokaryotic maintenance activities in terms of morphological and metabolic adaptations at low (winter) and high productivity (summer) are still unclear. To address this, we examined the natural prokaryotic communities at the mesocosm scale to analyse the differences in their morphological features and gene expression at low and high maintenance respiration, experimentally manipulated with the specific growth rate. Here, we showed that morphological features including membrane blebbing, membrane vesicles, and cell-cell connections occurred under high productivity. Metabolic adaptations associated with maintenance activities were observed under low productivity. Several Kyoto Encyclopedia of Genes and Genomes categories related to signal transduction, energy metabolism, and translational machinery supported maintenance activities under simulated winter conditions. Differential abundances of genes related to transporters, osmoregulation, nitrogen metabolism, ribosome biogenesis, and cold stress were observed. Our results demonstrate how specific growth rate in different seasons can influence resource allocation at the levels of morphological features and metabolic adaptations. This motivates further study of morphological features and their ecological role during high productivity, while investigations of metabolic adaptations during low productivity can advance our knowledge about maintenance activities.

Place, publisher, year, edition, pages
Oxford University Press, 2024
Keywords
cell shape, maintenance activities, mesocosm, morphology, prokaryotes, respiration
National Category
Botany
Identifiers
urn:nbn:se:umu:diva-232389 (URN)10.1093/femsec/fiae121 (DOI)001353211300001 ()39264060 (PubMedID)2-s2.0-85208997800 (Scopus ID)
Funder
The Kempe Foundations, SMK-185EU, Horizon 2020, 731065
Available from: 2024-12-02 Created: 2024-12-02 Last updated: 2024-12-02Bibliographically approved
Oscarsson, J., Bao, K., Shiratsuchi, A., Grossmann, J., Wolski, W., Aung, K. M., . . . Bostanci, N. (2024). Protocol for analyzing the function of the type VI secretion system of the oral symbiont Aggregatibacter aphrophilus in targeting pathobionts. STAR Protocols, 5(4), Article ID 103415.
Open this publication in new window or tab >>Protocol for analyzing the function of the type VI secretion system of the oral symbiont Aggregatibacter aphrophilus in targeting pathobionts
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2024 (English)In: STAR Protocols, E-ISSN 2666-1667, Vol. 5, no 4, article id 103415Article in journal (Refereed) Published
Abstract [en]

Here, we present a protocol for evaluating type VI secretion system (T6SS)dependent fitness of the oral symbiont A. aphrophilus using biofilm competition assays and metaproteomics. We describe steps for designing T6SS-specific mutants. We then detail procedures for using them in competition assays with the pathobiont A.actinomycetemcomitans and in biofilm models, analyzing metaproteomes to assess the impact of the T6SS on multiple pathobionts. The biofilm modelis designed to mimic the oral plaque ecosystem and includes seven species. For complete details on the use and execution of this protocol, please refer to Oscarsson et al.

Place, publisher, year, edition, pages
Cell Press, 2024
Keywords
Bacteriology, Microbial flora, Microbial interactions
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Microbiology
Identifiers
urn:nbn:se:umu:diva-231244 (URN)10.1016/j.xpro.2024.103415 (DOI)001344680300001 ()39460940 (PubMedID)2-s2.0-85207348303 (Scopus ID)
Funder
Swedish Research Council, 2017-01198, 2021-03528Region Västerbotten, 7002667Umeå UniversityKarolinska Institute
Available from: 2024-10-28 Created: 2024-10-28 Last updated: 2025-03-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4793-4671

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