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Publications (10 of 14) Show all publications
Pu, L., Wang, J., Lu, Q., Nilsson, L., Philbrook, A., Pandey, A., . . . Chen, C. (2023). Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in  C. elegans. Nature Communications, 14, Article ID 8410.
Open this publication in new window or tab >>Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in  C. elegans
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, article id 8410Article in journal (Refereed) Published
Abstract [en]

G protein-coupled receptors (GPCRs) mediate responses to various extracellular and intracellular cues. However, the large number of GPCR genes and their substantial functional redundancy make it challenging to systematically dissect GPCR functions in vivo. Here, we employ a CRISPR/Cas9-based approach, disrupting 1654 GPCR-encoding genes in 284 strains and mutating 152 neuropeptide-encoding genes in 38 strains in C. elegans. These two mutant libraries enable effective deorphanization of chemoreceptors, and characterization of receptors for neuropeptides in various cellular processes. Mutating a set of closely related GPCRs in a single strain permits the assignment of functions to GPCRs with functional redundancy. Our analyses identify a neuropeptide that interacts with three receptors in hypoxia-evoked locomotory responses, unveil a collection of regulators in pathogen-induced immune responses, and define receptors for the volatile food-related odorants. These results establish our GPCR and neuropeptide mutant libraries as valuable resources for the C. elegans community to expedite studies of GPCR signaling in multiple contexts.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-217489 (URN)10.1038/s41467-023-44177-z (DOI)38110404 (PubMedID)2-s2.0-85180225404 (Scopus ID)
Funder
Swedish Research Council, 2018-02914Swedish Research Council, 2021-06602Swedish Research Council, 2018-02216
Note

Originally included in thesis in manuscript form. 

Available from: 2023-12-05 Created: 2023-12-05 Last updated: 2024-01-05Bibliographically approved
Mihai, I. S., Chafle, S. & Henriksson, J. (2023). Representing and extracting knowledge from single-cell data. Biophysical Reviews
Open this publication in new window or tab >>Representing and extracting knowledge from single-cell data
2023 (English)In: Biophysical Reviews, ISSN 1867-2450Article, review/survey (Refereed) Published
Abstract [en]

Single-cell analysis is currently one of the most high-resolution techniques to study biology. The large complex datasets that have been generated have spurred numerous developments in computational biology, in particular the use of advanced statistics and machine learning. This review attempts to explain the deeper theoretical concepts that underpin current state-of-the-art analysis methods. Single-cell analysis is covered from cell, through instruments, to current and upcoming models. The aim of this review is to spread concepts which are not yet in common use, especially from topology and generative processes, and how new statistical models can be developed to capture more of biology. This opens epistemological questions regarding our ontology and models, and some pointers will be given to how natural language processing (NLP) may help overcome our cognitive limitations for understanding single-cell data.

Keywords
Generating processes, Graphs, Graphs, Markov chains, Neural networks, NLP, Single-cell, Statistics, Topology, VAE
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-212821 (URN)10.1007/s12551-023-01091-4 (DOI)001060089100001 ()2-s2.0-85166985324 (Scopus ID)
Funder
Swedish Research Council, 2021-06602
Available from: 2023-08-16 Created: 2023-08-16 Last updated: 2024-05-07Bibliographically approved
Hildebrandt, F., Mohammed, M., Dziedziech, A., Bhandage, A. K., Divne, A.-M., Barrenäs, F., . . . Ankarklev, J. (2023). scDual-Seq of Toxoplasma gondii-infected mouse BMDCs reveals heterogeneity and differential infection dynamics. Frontiers in Immunology, 14, Article ID 1224591.
Open this publication in new window or tab >>scDual-Seq of Toxoplasma gondii-infected mouse BMDCs reveals heterogeneity and differential infection dynamics
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1224591Article in journal (Refereed) Published
Abstract [en]

Dendritic cells and macrophages are integral parts of the innate immune system and gatekeepers against infection. The protozoan pathogen, Toxoplasma gondii, is known to hijack host immune cells and modulate their immune response, making it a compelling model to study host-pathogen interactions. Here we utilize single cell Dual RNA-seq to parse out heterogeneous transcription of mouse bone marrow-derived dendritic cells (BMDCs) infected with two distinct genotypes of T. gondii parasites, over multiple time points post infection. We show that the BMDCs elicit differential responses towards T. gondii infection and that the two parasite lineages distinctly manipulate subpopulations of infected BMDCs. Co-expression networks define host and parasite genes, with implications for modulation of host immunity. Integrative analysis validates previously established immune pathways and additionally, suggests novel candidate genes involved in host-pathogen interactions. Altogether, this study provides a comprehensive resource for characterizing host-pathogen interplay at high-resolution.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
BMDCs, bone marrow-derived dendritic cells, Dual single-cell RNA-seq, host-pathogen interactions, immune modulation, scDual-Seq, Toxoplasma gondii
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-213060 (URN)10.3389/fimmu.2023.1224591 (DOI)001045246300001 ()37575232 (PubMedID)2-s2.0-85167593817 (Scopus ID)
Funder
Swedish Research Council, 2021-05057Swedish Research Council, 2021- 06602Swedish Research Council, 2018-0241Swedish Research Council, 2022-00520Sven och Lilly Lawskis fond för naturvetenskaplig forskning
Available from: 2023-08-24 Created: 2023-08-24 Last updated: 2024-01-17Bibliographically approved
Mohammed, M., Dziedziech, A., Sekar, V., Ernest, M., Alves E Silva, T. L., Balan, B., . . . Ankarklev, J. (2023). Single-cell transcriptomics to define Plasmodium falciparum stage transition in the mosquito midgut. Microbiology Spectrum, 11(2)
Open this publication in new window or tab >>Single-cell transcriptomics to define Plasmodium falciparum stage transition in the mosquito midgut
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2023 (English)In: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 11, no 2Article in journal (Refereed) Published
Abstract [en]

Malaria inflicts the highest rate of morbidity and mortality among the vector-borne diseases. The dramatic bottleneck of parasite numbers that occurs in the gut of the obligatory mosquito vector provides a promising target for novel control strategies. Using single-cell transcriptomics, we analyzed Plasmodium falciparum development in the mosquito gut, from unfertilized female gametes through the first 20 h after blood feeding, including the zygote and ookinete stages. This study revealed the temporal gene expression of the ApiAP2 family of transcription factors and of parasite stress genes in response to the harsh environment of the mosquito midgut. Further, employing structural protein prediction analyses, we found several upregulated genes predicted to encode intrinsically disordered proteins (IDPs), a category of proteins known for their importance in regulation of transcription, translation, and protein-protein interactions. IDPs are known for their antigenic properties and may serve as suitable targets for antibody- or peptide-based transmission suppression strategies. In total, this study uncovers the P. falciparum transcriptome from early to late parasite development in the mosquito midgut, inside its natural vector, which provides an important resource for future malaria transmission-blocking initiatives. IMPORTANCE The malaria parasite Plasmodium falciparum causes more than half a million deaths per year. The current treatment regimen targets the symptom-causing blood stage inside the human host. However, recent incentives in the field call for novel interventions to block parasite transmission from humans to the mosquito vector. Therefore, we need to better understand the parasite biology during its development inside the mosquito, including a deeper understanding of the expression of genes controlling parasite progression during these stages. Here, we have generated single-cell transcriptome data, covering P. falciparum’s development, from gamete to ookinete inside the mosquito midgut, uncovering previously untapped parasite biology, including a repertoire of novel biomarkers to be explored in future transmission-blocking efforts. We anticipate that our study provides an important resource, which can be further explored to improve our understanding of the parasite biology as well as aid in guiding future malaria intervention strategies.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023
Keywords
malaria, mosquito midgut, Plasmodium falciparum, scRNA-seq, single cell, stage transition, transmission
National Category
Cell and Molecular Biology Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-208221 (URN)10.1128/spectrum.03671-22 (DOI)000939731800001 ()36847501 (PubMedID)2-s2.0-85153879865 (Scopus ID)
Funder
NIH (National Institutes of Health), AI001250-01Harald Jeanssons stiftelseHarald and Greta Jeansson FoundationSwedish Society for Medical Research (SSMF)Swedish Research Council, 2018-05973NIH (National Institutes of Health), R01AI031478
Available from: 2023-05-12 Created: 2023-05-12 Last updated: 2023-10-06Bibliographically approved
Schoutrop, E., Poiret, T., El-Serafi, I., Zhao, Y., He, R., Moter, A., . . . Mattsson, J. (2023). Tuned activation of MSLN-CAR T cells induces superior antitumor responses in ovarian cancer models. Journal for ImmunoTherapy of Cancer, 11(2), Article ID e005691.
Open this publication in new window or tab >>Tuned activation of MSLN-CAR T cells induces superior antitumor responses in ovarian cancer models
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2023 (English)In: Journal for ImmunoTherapy of Cancer, E-ISSN 2051-1426, Vol. 11, no 2, article id e005691Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Limited persistence of functional CAR T cells in the immunosuppressive solid tumor microenvironment remains a major hurdle in the successful translation of CAR T cell therapy to treat solid tumors. Fine-tuning of CAR T cell activation by mutating CD3ζ chain immunoreceptor tyrosine-based activation motifs (ITAMs) in CD19-CAR T cells (containing the CD28 costimulatory domain) has proven to extend functional CAR T cell persistence in preclinical models of B cell malignancies.

METHODS: In this study, two conventional second-generation MSLN-CAR T cell constructs encoding for either a CD28 co-stimulatory (M28z) or 4-1BB costimulatory (MBBz) domain and a novel mesothelin (MSLN)-directed CAR T cell construct encoding for the CD28 costimulatory domain and CD3ζ chain containing a single ITAM (M1xx) were evaluated using in vitro and in vivo preclinical models of ovarian cancer. Two ovarian cancer cell lines and two orthotopic models of ovarian cancer in NSG mice were used: SKOV-3 cells inoculated through microsurgery in the ovary and to mimic a disseminated model of advanced ovarian cancer, OVCAR-4 cells injected intraperitoneally. MSLN-CAR T cell treatment efficacy was evaluated by survival analysis and the characterization and quantification of the different MSLN-CAR T cells were performed by flow cytometry, quantitative PCR and gene expression analysis.

RESULTS: M1xx CAR T cells elicited superior antitumor potency and persistence, as compared with the conventional second generation M28z and MBBz CAR T cells. Ex vivo M28z and MBBz CAR T cells displayed a more exhausted phenotype than M1xx CAR T cells as determined by co-expression of PD-1, LAG-3 and TIM-3. Furthermore, M1xx CAR T cells showed superior ex vivo IFNy, TNF and GzB production and were characterized by a self-renewal gene signature.

CONCLUSIONS: Altogether, our study demonstrates the enhanced therapeutic potential of MSLN-CAR T cells expressing a mutated CD3ζ chain containing a single ITAM for the treatment of ovarian cancer. CAR T cells armored with calibrated activation potential may improve the clinical responses in solid tumors.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2023
Keywords
Immunotherapy, Receptors, Chimeric Antigen
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-204743 (URN)10.1136/jitc-2022-005691 (DOI)000929376700001 ()36746513 (PubMedID)2-s2.0-85147460854 (Scopus ID)
Funder
The Karolinska Institutet's Research Foundation, 2020-01402Swedish Childhood Cancer Foundation, PR2017-0083The Cancer Research Funds of Radiumhemmet, 161082Swedish Research Council, 2021-06602Swedish Cancer Society, 19 0002 FESwedish Cancer Society, 21 1465 PThe Cancer Research Funds of Radiumhemmet, 201232The Karolinska Institutet's Research Foundation, 2020-01354Swedish Research Council, 19 0359 Pj 01 H9The Cancer Research Funds of Radiumhemmet, 181201
Available from: 2023-02-22 Created: 2023-02-22 Last updated: 2023-09-05Bibliographically approved
Chotiwan, N., Rosendal, E., Willekens, S. M. A., Schexnaydre, E., Nilsson, E., Lindquist, R., . . . Överby, A. K. (2023). Type I interferon shapes brain distribution and tropism of tick-borne flavivirus. Nature Communications, 14(1), Article ID 2007.
Open this publication in new window or tab >>Type I interferon shapes brain distribution and tropism of tick-borne flavivirus
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 2007Article in journal (Refereed) Published
Abstract [en]

Viral tropism within the brain and the role(s) of vertebrate immune response to neurotropic flaviviruses infection is largely understudied. We combine multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype and interferon alpha/beta receptor knockout (Ifnar-/-) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection is imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection is limited to grey matter of sensory systems in wildtype mice, but extends into white matter, meninges and choroid plexus in Ifnar-/- mice. Cells in wildtype display strong type I and II IFN responses, likely due to Ifnb expressing astrocytes, infiltration of macrophages and Ifng-expressing CD8+ NK cells, whereas in Ifnar-/-, the absence of this response contributes to a shift in cellular tropism towards non-activated resident microglia. Multimodal imaging-transcriptomics exemplifies a powerful way to characterize mechanisms of viral pathogenesis and tropism.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Neurosciences
Identifiers
urn:nbn:se:umu:diva-206780 (URN)10.1038/s41467-023-37698-0 (DOI)000967732600009 ()37037810 (PubMedID)2-s2.0-85152115180 (Scopus ID)
Funder
The Kempe Foundations, SMK-1532Knut and Alice Wallenberg Foundation, KAW2015.0284Swedish Research Council, 2018-05851Swedish Research Council, 2017-01307Swedish Research Council, 2020-06224Swedish Research Council, 2021-06602
Available from: 2023-04-24 Created: 2023-04-24 Last updated: 2023-09-05Bibliographically approved
Rosendal, E., Mihai, I. S., Becker, M., Das, D., Frängsmyr, L., Persson, B. D., . . . Lenman, A. (2022). Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections. mBio, 13(3), Article ID e00892-22.
Open this publication in new window or tab >>Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections
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2022 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 13, no 3, article id e00892-22Article in journal (Refereed) Published
Abstract [en]

The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal outcome. Individual factors such as age, sex, and comorbidities increase the risk for severe infections, but other aspects, such as genetic variations, are also likely to affect the susceptibility to SARS-CoV-2 infection and disease severity. Here, we used a human 3D lung cell model based on primary cells derived from multiple donors to identity host factors that regulate SARS-CoV-2 infection. With a transcriptomics-based approach, we found that less susceptible donors show a higher expression level of serine protease inhibitors SERPINA1, SERPINE1, and SERPINE2, identifying variation in cellular serpin levels as restricting host factors for SARS-CoV-2 infection. We pinpoint their antiviral mechanism of action to inhibition of the cellular serine protease, TMPRSS2, thereby preventing cleavage of the viral spike protein and TMPRSS2-mediated entry into the target cells. By means of single-cell RNA sequencing, we further locate the expression of the individual serpins to basal, ciliated, club, and goblet cells. Our results add to the importance of genetic variations as determinants for SARS-CoV-2 susceptibility and suggest that genetic deficiencies of cellular serpins might represent risk factors for severe COVID-19. Our study further highlights TMPRSS2 as a promising target for antiviral intervention and opens the door for the usage of locally administered serpins as a treatment against COVID-19.

Place, publisher, year, edition, pages
American Society for Microbiology, 2022
Keywords
A1AT, alpha-1-antitrypsin, antithrombin III, ATIII, COVID-19, PAI1, plasminogen activator inhibitor 1, SARS-CoV-2, serpin, TMPRSS2
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-203186 (URN)10.1128/mbio.00892-22 (DOI)000797888900001 ()35532162 (PubMedID)2-s2.0-85133144334 (Scopus ID)
Funder
Science for Life Laboratory, SciLifeLabSwedish National Infrastructure for Computing (SNIC), SNIC 2020/6-251Swedish Heart Lung Foundation, 2020038Knut and Alice Wallenberg Foundation, 2020.0182Knut and Alice Wallenberg Foundation, C19R:028Swedish Society for Medical Research (SSMF)The Kempe Foundations, JCK-1827Swedish Research Council, 2016-06598
Available from: 2023-01-17 Created: 2023-01-17 Last updated: 2023-07-03Bibliographically approved
Mihai, I. S., Das, D., Maršalkaite, G. & Henriksson, J. (2021). Meta-analysis of gene popularity: Less than half of gene citations stem from gene regulatory networks. Genes, 12(2), 1-13, Article ID 319.
Open this publication in new window or tab >>Meta-analysis of gene popularity: Less than half of gene citations stem from gene regulatory networks
2021 (English)In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 2, p. 1-13, article id 319Article in journal (Refereed) Published
Abstract [en]

The reasons for selecting a gene for further study might vary from historical momentum to funding availability, thus leading to unequal attention distribution among all genes. However, certain biological features tend to be overlooked in evaluating a gene’s popularity. Here we present a meta-analysis of the reasons why different genes have been studied and to what extent, with a focus on the gene-specific biological features. From unbiased datasets we can define biological properties of genes that reasonably may affect their perceived importance. We make use of both linear and nonlinear computational approaches for estimating gene popularity to then compare their relative importance. We find that roughly 25% of the studies are the result of a historical positive feedback, which we may think of as social reinforcement. Of the remaining features, gene family membership is the most indicative followed by disease relevance and finally regulatory pathway association. Disease relevance has been an important driver until the 1990s, after which the focus shifted to exploring every single gene. We also present a resource that allows one to study the impact of reinforcement, which may guide our research toward genes that have not yet received proportional attention.

Place, publisher, year, edition, pages
mdpi, 2021
Keywords
Biological feature, Gene, Gene regulatory networks, Genomics, Linear model, Machine learning, Matthew effect
National Category
Bioinformatics and Systems Biology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-181735 (URN)10.3390/genes12020319 (DOI)000622602900001 ()2-s2.0-85102335494 (Scopus ID)
Available from: 2021-03-23 Created: 2021-03-23 Last updated: 2023-09-05Bibliographically approved
Dernstedt, A., Leidig, J., Holm, A., Kerkman, P., Mjösberg, J., Ahlm, C., . . . Forsell, M. N. E. (2021). Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis. Frontiers in Immunology, 11, Article ID 599647.
Open this publication in new window or tab >>Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis
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2021 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, article id 599647Article in journal (Refereed) Published
Abstract [en]

Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition on host cells and therefore also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR engagement and that T cell-dependent stimuli preferentially led to activation of DAF(lo) B cells. Consistent with this, a majority of light and dark zone GC B cells were DAF(lo) and susceptible to complement-dependent phagocytosis, as compared with DAF(hi) GC B cells. We could also show that the DAF(hi) GC B cell subset had increased expression of the plasma cell marker Blimp-1. DAF expression was also modulated during B cell hematopoiesis in the human bone marrow. Collectively, our results reveal a novel role of DAF to pre-prime activated human B cells for phagocytosis prior to apoptosis.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021
Keywords
human B cell development, germinal center (GC), decay accelerating factor (DAF), complement-mediated phagocytosis, complement regulating proteins
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-179577 (URN)10.3389/fimmu.2020.599647 (DOI)000608470700001 ()33469456 (PubMedID)2-s2.0-85099651060 (Scopus ID)
Funder
NIH (National Institute of Health), U19AI142777-01Swedish Research Council, 2016-06598
Available from: 2021-02-04 Created: 2021-02-04 Last updated: 2024-01-17Bibliographically approved
Jafari, S., Henriksson, J., Yan, H. & Alenius, M. (2021). Stress and odorant receptor feedback during a critical period after hatching regulates olfactory sensory neuron differentiation in Drosophila. PLoS biology, 19(4), Article ID e3001101.
Open this publication in new window or tab >>Stress and odorant receptor feedback during a critical period after hatching regulates olfactory sensory neuron differentiation in Drosophila
2021 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 19, no 4, article id e3001101Article in journal (Refereed) Published
Abstract [en]

Here, we reveal that the regulation of Drosophila odorant receptor (OR) expression during the pupal stage is permissive and imprecise. We found that directly after hatching an OR feedback mechanism both directs and refines OR expression. We demonstrate that, as in mice, dLsd1 and Su(var)3-9 balance heterochromatin formation to direct OR expression. We show that the expressed OR induces dLsd1 and Su(var)3-9 expression, linking OR level and possibly function to OR expression. OR expression refinement shows a restricted duration, suggesting that a gene regulatory critical period brings olfactory sensory neuron differentiation to an end. Consistent with a change in differentiation, stress during the critical period represses dLsd1 and Su(var)3-9 expression and makes the early permissive OR expression permanent. This induced permissive gene regulatory state makes OR expression resilient to stress later in life. Hence, during a critical period OR feedback, similar to in mouse OR selection, defines adult OR expression in Drosophila.

Place, publisher, year, edition, pages
Public Library of Science, 2021
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-182748 (URN)10.1371/JOURNAL.PBIO.3001101 (DOI)000636466700002 ()33793547 (PubMedID)2-s2.0-85104276130 (Scopus ID)
Available from: 2021-05-24 Created: 2021-05-24 Last updated: 2023-09-05Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7745-2844

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