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Article ; Online: Contribution of transcription to animal early development.

Wang, Jianbin / Davis, Richard E

2014 Volume 5, Issue 4, Page(s) e967602

Abstract: In mature gametes and during the oocyte-to-embryo transition, transcription is generally silenced ... transcription can occur immediately after fertilization, prior to pronuclear fusion, and in the first ... and gene expression is post-transcriptionally regulated. However, we recently discovered that major ...

Abstract	In mature gametes and during the oocyte-to-embryo transition, transcription is generally silenced and gene expression is post-transcriptionally regulated. However, we recently discovered that major transcription can occur immediately after fertilization, prior to pronuclear fusion, and in the first cell division of the oocyte-to-embryo transition in the nematode Ascaris suum. We postulate that the balance between transcriptional and post-transcriptional regulation during the oocyte-to-embryo transition may largely be determined by cell cycle length and thus the time available for the genome to be transcribed.
MeSH term(s)	Animals ; Ascaris/genetics ; Ascaris/growth & development ; Ascaris/metabolism ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/growth & development ; Caenorhabditis elegans/metabolism ; Cell Cycle Checkpoints ; Embryonic Development ; Gene Expression Regulation, Developmental ; Oocytes/growth & development ; Oocytes/metabolism ; Protein Processing, Post-Translational ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Transcription, Genetic ; Xenopus/genetics ; Xenopus/growth & development ; Xenopus/metabolism ; Zygote/growth & development ; Zygote/metabolism
Chemical Substances	RNA-Binding Proteins
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2646974-1
ISSN	2154-1272 ; 2154-1264
ISSN (online)	2154-1272
ISSN	2154-1264
DOI	10.4161/21541264.2014.967602
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Article ; Online: Enrichment of type 1 innate lymphoid cells in the course of human atherosclerotic plaque development suggests contribution to atherogenesis.

Pertiwi, Kartika R / Teunissen, Marcel B M / Krebbers, Gabrielle / Willems, Martine C M / Huisman, Laurens / Poelen, Cindy / van der Wal, Allard C / de Boer, Onno J

Frontiers in immunology

2024 Volume 15, Page(s) 1354617

Abstract: ... in humans remains unexplored.: Methods: Here, we identify ILCs and their dynamics in early, advanced, and ... significantly outnumbered their ILC counterparts, except for the early lesions where the proportion of ILC1s was ... markedly higher, albeit not significant.: Discussion: The high abundance of ILC1s in the early stages ...

Abstract	Introduction: Innate lymphoid cells (ILCs) have been implicated in multiple pathologic conditions, including atherogenesis, as documented in experimental mice studies, however, their role in atherosclerosis in humans remains unexplored. Methods: Here, we identify ILCs and their dynamics in early, advanced, and complicated human carotid- and aortic atherosclerotic plaques, using a multiplex immunohistochemical quadruple-staining technique with prototypic transcription factors T-bet, GATA3, or RORgt for identification of the ILC1, ILC2 and ILC3 subsets, respectively, in combination with lineage markers CD3, CD20/ CD79a and CD56 to exclude other lymphoid cell types. ILC subsets were quantified, and to put this in perspective, their numbers were expressed as percentage of the total number of infiltrated lymphoid cells and related to the frequency of conventional T cells, B cells, NK cells, and NKT cells. Results: All ILC subsets were present in every different stage of atherogenesis. ILC1s were the most abundant ILC subset, and their numbers significantly increased in the course of plaque development, but paradoxically, their relative frequency was reduced because of a higher increment of T cells and B cells. The numbers of ILC2s and ILC3s also gradually increased, but this trend did not achieve significance. T cell subsets always significantly outnumbered their ILC counterparts, except for the early lesions where the proportion of ILC1s was markedly higher, albeit not significant. Discussion: The high abundance of ILC1s in the early stages and further significant enrichment in later stages, suggest they may participate in the initiation and development of atherogenesis, and thus, may represent a novel target to prevent or treat atherosclerosis.
MeSH term(s)	Humans ; Mice ; Animals ; Immunity, Innate ; Plaque, Atherosclerotic ; Killer Cells, Natural ; Atherosclerosis
Language	English
Publishing date	2024-04-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1354617
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Article ; Online: Functional contribution of DCLKs in sea urchin development.

Xu, Derek / Wavreil, Florence D M / Waldron, Ashley / Yajima, Mamiko

Developmental dynamics : an official publication of the American Association of Anatomists

2021 Volume 250, Issue 8, Page(s) 1160–1172

Abstract: ... during early embryogenesis and with some enrichment in mesenchymal cells after gastrula stage. Knockdown ... for neuronal development. More recently, they are also reported to regulate plasticity ... regulation, we here used the sea urchin embryo that undergoes highly regulative development ...

Abstract	Background: Doublecortin-like kinase1 and 2 (DCLKs) are protein Ser/Thr kinases important for neuronal development. More recently, they are also reported to regulate plasticity such as cell proliferation and differentiation of stem cells and cancer cells, but the details of their functions in this biological context are still unclear. With an attempt to reveal the functions of DCLKs in plasticity regulation, we here used the sea urchin embryo that undergoes highly regulative development as an experimental model. Results: We found that both the transcripts and the proteins of DCLKs are uniformly present during early embryogenesis and with some enrichment in mesenchymal cells after gastrula stage. Knockdown of DCLKs induced general developmental delay and defects at day 2. Further, the damage on the embryo/larva induced ectopic expression of DCLKs in the ectoderm where the damage was most severe. Under a tumor-prone or -suppressive condition, DCLKs expression was upregulated or downregulated, respectively, after damage. In both cases, the embryos showed severe developmental defects. Conclusions: Taken together, a transient upregulation of DCLKs appears to be involved in a damage response both during normal and abnormal development, and which could result in different phenotypes in a context dependent manner.
MeSH term(s)	Animals ; Cell Differentiation/physiology ; Doublecortin-Like Kinases/genetics ; Doublecortin-Like Kinases/metabolism ; Embryo, Nonmammalian/metabolism ; Embryonic Development/physiology ; Gene Expression Regulation, Developmental ; Sea Urchins/genetics ; Sea Urchins/metabolism
Chemical Substances	Doublecortin-Like Kinases (EC 2.7.1.11)
Language	English
Publishing date	2021-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1102541-4
ISSN	1097-0177 ; 1058-8388
ISSN (online)	1097-0177
ISSN	1058-8388
DOI	10.1002/dvdy.316
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Article ; Online: Contribution of sox9b to pigment cell formation in medaka fish.

Tsunogai, Yuri / Miyadai, Motohiro / Nagao, Yusuke / Sugiwaka, Keisuke / Kelsh, Robert N / Hibi, Masahiko / Hashimoto, Hisashi

Development, growth & differentiation

2021 Volume 63, Issue 9, Page(s) 516–522

Abstract: SoxE-type transcription factors, Sox10 and Sox9, are key regulators of the development ... lethality at the early larval stages. By using sox10a, sox10b, and sox9b mutations, compound mutants were ...

Abstract	SoxE-type transcription factors, Sox10 and Sox9, are key regulators of the development of neural crest cells. Sox10 specifies pigment cell, glial, and neuronal lineages, whereas Sox9 is reportedly closely associated with skeletogenic lineages in the head, but its involvement in pigment cell formation has not been investigated genetically. Thus, it is not fully understood whether or how distinctly these genes as well as their paralogs in teleosts are subfunctionalized. We have previously shown using the medaka fish Oryzias latipes that pigment cell formation is severely affected by the loss of sox10a, yet unaffected by the loss of sox10b. Here we aimed to determine whether Sox9 is involved in the specification of pigment cell lineage. The sox9b homozygous mutation did not affect pigment cell formation, despite lethality at the early larval stages. By using sox10a, sox10b, and sox9b mutations, compound mutants were established for the sox9b and sox10 genes and pigment cell phenotypes were analyzed. Simultaneous loss of sox9b and sox10a resulted in the complete absence of melanophores and xanthophores from hatchlings and severely defective iridophore formation, as has been previously shown for sox10a
MeSH term(s)	Animals ; Cell Lineage ; Melanophores ; Neural Crest ; Oryzias/genetics ; Oryzias/growth & development ; SOX9 Transcription Factor/genetics
Chemical Substances	SOX9 Transcription Factor
Language	English
Publishing date	2021-12-09
Publishing country	Japan
Document type	Journal Article
ZDB-ID	280433-5
ISSN	1440-169X ; 0012-1592
ISSN (online)	1440-169X
ISSN	0012-1592
DOI	10.1111/dgd.12760
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Article ; Online: Contribution of Gut Microbiota to Immune Tolerance in Infants.

Méndez, Constanza S / Bueno, Susan M / Kalergis, Alexis M

Journal of immunology research

2021 Volume 2021, Page(s) 7823316

Abstract: ... characteristics are acquired through environmental interactions starting early in life, such as type of delivery ... mechanisms, including a predominant role of Tregs and the transcription factor FOXP3. Additionally, a pivotal ... These observations have led to the study and development of therapies oriented to modifying the microbiota and ...

Abstract	The prevalence of food allergy has increased in recent years, especially among the pediatric population. Differences in the gut microbiota composition between children with FA and healthy children have brought this topic into the spotlight as a possible explanation for the increase in FA. The gut microbiota characteristics are acquired through environmental interactions starting early in life, such as type of delivery during birth and breastfeeding. The microbiota features may be shaped by a plethora of immunomodulatory mechanisms, including a predominant role of Tregs and the transcription factor FOXP3. Additionally, a pivotal role has been given to vitamin A and butyrate, the main anti-inflammatory metabolite. These observations have led to the study and development of therapies oriented to modifying the microbiota and metabolite profiles, such as the use of pre- and probiotics and the determination of their capacity to induce tolerance to allergens that are relevant to FA. To date, evidence supporting these approaches in humans is scarce and inconclusive. Larger cohorts and dose-titration studies are mandatory to evaluate whether the observed changes in gut microbiota composition reflect medical recovery and increased tolerance in pediatric patients with FA. In this article, we discuss the establishment of the microbiota, the immunological mechanisms that regulate the microbiota of children with food allergies, and the evidence in research focused on its regulation as a means to achieve tolerance to food allergens.
MeSH term(s)	Age Factors ; Animals ; Biomarkers ; Disease Management ; Disease Susceptibility ; Dysbiosis ; Energy Metabolism ; Female ; Gastrointestinal Microbiome/immunology ; Host Microbial Interactions/immunology ; Humans ; Hypersensitivity/diagnosis ; Hypersensitivity/etiology ; Hypersensitivity/metabolism ; Hypersensitivity/therapy ; Immune System/immunology ; Immune System/metabolism ; Immune Tolerance ; Immunity, Innate ; Infant ; Infant, Newborn ; Lymphocyte Subsets/immunology ; Lymphocyte Subsets/metabolism ; Male ; Mast Cells/immunology ; Mast Cells/metabolism ; Maternal-Fetal Exchange/immunology ; Pregnancy
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-12-28
Publishing country	Egypt
Document type	Journal Article ; Review
ZDB-ID	2817541-4
ISSN	2314-7156 ; 2314-7156
ISSN (online)	2314-7156
ISSN	2314-7156
DOI	10.1155/2021/7823316
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Article ; Online: Contribution of Signal Transducer and Activator of Transcription 3 (STAT3) to Bone Development and Repair.

Sobah, Mohamed L / Liongue, Clifford / Ward, Alister C

International journal of molecular sciences

2023 Volume 25, Issue 1

Abstract: ... length in early embryos exacerbated by a decreased growth rate from 5 days postfertilization (dpf ... in early bone but not cartilage formation. Further analysis additionally identified considerable abrogation ... that loss of canonical STAT3 signaling was the likely cause. However, the impacts on early bone formation ...

Abstract	Signal transducer and activator of transcription 3 (STAT3) is a transcription factor activated canonically by numerous cytokines and other factors, with significant roles in immunity, immune diseases, and cancer. It has also been implicated in several human skeletal disorders, with loss-of-function (LOF) mutations associated with aberrant skeletal development. To gain further insights, two zebrafish STAT3 lines were investigated: a complete LOF knockout (KO) mutant and a partial LOF mutant with the transactivation domain truncated (ΔTAD). Consistent with other studies, the KO mutants were smaller, with reduced length in early embryos exacerbated by a decreased growth rate from 5 days postfertilization (dpf). They displayed skeletal deformities that approached 80% incidence by 30 dpf, with a significant reduction in early bone but not cartilage formation. Further analysis additionally identified considerable abrogation of caudal fin regeneration, concomitant with a paucity of infiltrating macrophages and neutrophils, which may be responsible for this. Most of these phenotypes were also observed in the ΔTAD mutants, indicating that loss of canonical STAT3 signaling was the likely cause. However, the impacts on early bone formation and regeneration were muted in the ΔTAD mutant, suggesting the potential involvement of noncanonical functions in these processes.
MeSH term(s)	Animals ; Humans ; Bone Development/genetics ; Chondrogenesis ; Osteogenesis/genetics ; STAT3 Transcription Factor/genetics ; Zebrafish/genetics
Chemical Substances	STAT3 protein, human ; STAT3 Transcription Factor ; stat3 protein, zebrafish
Language	English
Publishing date	2023-12-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25010389
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Article ; Online: The contribution of glial cells to Huntington's disease pathogenesis.

Wilton, Daniel K / Stevens, Beth

Neurobiology of disease

2020 Volume 143, Page(s) 104963

Abstract: ... but in many neurodegenerative diseases, they become dysregulated and may contribute to the development of brain pathology ... that glial cell dysfunction occurs at a very early stage of the disease, prior to the onset of motor and cognitive ... Glial cells play critical roles in the normal development and function of neural circuits ...

Abstract	Glial cells play critical roles in the normal development and function of neural circuits, but in many neurodegenerative diseases, they become dysregulated and may contribute to the development of brain pathology. In Huntington's disease (HD), glial cells both lose normal functions and gain neuropathic phenotypes. In addition, cell-autonomous dysfunction elicited by mutant huntingtin (mHTT) expression in specific glial cell types is sufficient to induce both pathology and Huntington's disease-related impairments in motor and cognitive performance, suggesting that these cells may drive the development of certain aspects of Huntington's disease pathogenesis. In support of this imaging studies in pre-symptomatic HD patients and work on mouse models have suggested that glial cell dysfunction occurs at a very early stage of the disease, prior to the onset of motor and cognitive deficits. Furthermore, selectively ablating mHTT from specific glial cells or correcting for HD-induced changes in their transcriptional profile rescues some HD-related phenotypes, demonstrating the potential of targeting these cells for therapeutic intervention. Here we review emerging research focused on understanding the involvement of different glial cell types in specific aspects of HD pathogenesis. This work is providing new insight into how HD impacts biological functions of glial cells in the healthy brain as well as how HD induced dysfunction in these cells might change the way they integrate into biological circuits.
MeSH term(s)	Animals ; Brain/pathology ; Humans ; Huntington Disease/pathology ; Neuroglia/pathology
Language	English
Publishing date	2020-06-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2020.104963
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Article ; Online: The contribution of epididymosomes to the sperm small RNA profile.

Trigg, Natalie A / Eamens, Andrew L / Nixon, Brett

Reproduction (Cambridge, England)

2019 Volume 157, Issue 6, Page(s) R209–R223

Abstract: ... are able to influence both early embryonic development and the subsequent health of the offspring ... are rendered transcriptionally and translationally silent during their development in the testes ... of epididymosome-sperm communication in contributing to the establishment of the sperm sRNA profile during ...

Abstract	It is now well established that mature spermatozoa harbour a rich and diverse profile of small non-protein-coding regulatory RNAs (sRNAs). There is also growing appreciation that this sRNA profile displays considerable plasticity, being altered in response to paternal exposure to a variety of environmental stressors. Coupled with evidence that upon delivery to the oocyte at the moment of fertilisation, sperm-borne sRNAs are able to influence both early embryonic development and the subsequent health of the offspring, there is now interest in both the timing and degree of change in the composition of the sRNA cargo of sperm. Models in which such epigenetic changes are linked to the spermatogenic cycle are seemingly incompatible with the lack of overt phenotypic changes in the spermatozoa of affected males. Rather, there is mounting consensus that such changes are imposed on sperm during their transit and storage within the epididymis, a protracted developmental window that takes place over several weeks. Notably, since spermatozoa are rendered transcriptionally and translationally silent during their development in the testes, it is most likely that the epididymis-documented alterations to the sperm sRNA profile are driven extrinsically, with a leading candidate being epididymosomes: small membrane enclosed extracellular vesicles that encapsulate a complex macromolecular cargo of proteins and RNAs, including the sRNAs. Here, we review the role of epididymosome-sperm communication in contributing to the establishment of the sperm sRNA profile during their epididymal transit.
MeSH term(s)	Animals ; Cell-Derived Microparticles/genetics ; Cell-Derived Microparticles/metabolism ; Epididymis/metabolism ; Epididymis/physiology ; Humans ; Male ; RNA, Small Untranslated/genetics ; Spermatogenesis ; Spermatozoa/metabolism ; Spermatozoa/physiology ; Transcriptome
Chemical Substances	RNA, Small Untranslated
Language	English
Publishing date	2019-02-19
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2034501-X
ISSN	1741-7899 ; 1470-1626 ; 1476-3990
ISSN (online)	1741-7899
ISSN	1470-1626 ; 1476-3990
DOI	10.1530/REP-18-0480
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Article ; Online: Assessing Myf5 and Lbx1 contribution to carapace development by reproducing their turtle-specific signatures in mouse embryos.

Tekko, Triin / Lozovska, Anastasiia / Nóvoa, Ana / Mallo, Moisés

Developmental dynamics : an official publication of the American Association of Anatomists

2022 Volume 251, Issue 10, Page(s) 1698–1710

Abstract: ... exon 2 replicated some early properties of turtle somites, but still developed into viable and fertile ... engage in the development of a standard tetrapod ribcage in the absence of those signals. In addition ... genetic approaches in mouse embryos. At mid-gestation, mouse embryos producing Myf5 transcripts lacking ...

Abstract	Background: The turtle carapace is an evolutionary novelty resulting from changes in the processes that build ribs and their associated muscles in most tetrapod species. Turtle embryos have several unique features that might play a role in this process, including the carapacial ridge, a Myf5 gene with shorter coding region that generates an alternative splice variant lacking exon 2, and unusual expression patterns of Lbx1 and HGF. Results: We investigated these turtle-specific expression differences using genetic approaches in mouse embryos. At mid-gestation, mouse embryos producing Myf5 transcripts lacking exon 2 replicated some early properties of turtle somites, but still developed into viable and fertile mice. Extending Lbx1 expression into the hypaxial dermomyotomal lip of trunk somites to mimic the turtle Lbx1 expression pattern, produced fusions in the distal part of the ribs. Conclusions: Turtle-like Myf5 activity might generate a plastic state in developing trunk somites under which they can either enter carapace morphogenetic routes, possibly triggered by signals from the carapacial ridge, or still engage in the development of a standard tetrapod ribcage in the absence of those signals. In addition, trunk Lbx1 expression might play a later role in the formation of the lateral border of the carapace.
MeSH term(s)	Animal Shells ; Animals ; Biological Evolution ; Mice ; Myogenic Regulatory Factor 5/genetics ; Myogenic Regulatory Factor 5/metabolism ; Plastics/metabolism ; Somites ; Turtles/genetics
Chemical Substances	Myf5 protein, mouse ; Myogenic Regulatory Factor 5 ; Plastics
Language	English
Publishing date	2022-06-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1102541-4
ISSN	1097-0177 ; 1058-8388
ISSN (online)	1097-0177
ISSN	1058-8388
DOI	10.1002/dvdy.502
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Article ; Online: Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion.

Shao, Feng-Jin / Guo, Xiao-Ling / Xu, Jia-Xue / Liu, Rui / Li, Dan-Yue / Li, Qing-Hao / Zhou, Ting / Fang, Cun / Tan, Xun

Respiratory research

2022 Volume 23, Issue 1, Page(s) 290

Abstract: ... inflammation and dysfunction in early progenitor endothelial cells (eEPCs). We tested the hypothesis that eEPCs ... contribute to the development of plexiform lesions by differentiating into macrophages in the setting ... composed of the early lesions have a typical eEPC phenotype whereas those in more mature lesions display ...

Abstract	Background: Plexiform lesions, which have a dynamic appearance in structure and cellular composition, are the histological hallmark of severe pulmonary arterial hypertension in humans. The pathogenesis of the lesion development remains largely unknown, although it may be related to local inflammation and dysfunction in early progenitor endothelial cells (eEPCs). We tested the hypothesis that eEPCs contribute to the development of plexiform lesions by differentiating into macrophages in the setting of chronic inflammation. Methods: The eEPC markers CD133 and VEGFR-2, macrophage lineage marker mannose receptor C-type 1 (MRC1), TNFα and nuclear factor erythroid 2-related factor 2 (Nrf2) in plexiform lesions in a broiler model were determined by immunohistochemistry. eEPCs derived from peripheral blood mononuclear cells were exposed to TNFα, and macrophage differentiation and angiogenic capacity of the cells were evaluated by phagocytotic and Matrigel plug assays, respectively. The role of Nrf2 in eEPC-to-macrophage transition as well as in MRC1 expression was also evaluated. Intratracheal installation of TNFα was conducted to determine the effect of local inflammation on the formation of plexiform lesions. Results: Cells composed of the early lesions have a typical eEPC phenotype whereas those in more mature lesions display molecular and morphological characteristics of macrophages. Increased TNFα production in plexiform lesions was observed with lesion progression. In vitro studies showed that chronic TNFα challenge directed eEPCs to macrophage differentiation accompanied by hyperactivation of Nrf2, a stress-responsive transcription factor. Nrf2 activation (Keap1 knockdown) caused a marked downregulation in CD133 but upregulation in MRC1 mRNA. Dual luciferase reporter assay demonstrated that Nrf2 binds to the promoter of MRC1 to trigger its expression. In good agreement with the in vitro observation, TNFα exposure induced macrophage differentiation of eEPCs in Matrigel plugs, resulting in reduced neovascularization of the plugs. Intratracheal installation of TNFα resulted in a significant increase in plexiform lesion density. Conclusions: This work provides evidence suggesting that macrophage differentiation of eEPCs resulting from chronic inflammatory stimulation contributes to the development of plexiform lesions. Given the key role of Nrf2 in the phenotypic switching of eEPCs to macrophages, targeting this molecular might be beneficial for intervention of plexiform lesions.
MeSH term(s)	Animals ; Humans ; Endothelial Progenitor Cells/physiology ; Vascular Endothelial Growth Factor Receptor-2 ; Tumor Necrosis Factor-alpha ; NF-E2-Related Factor 2 ; Kelch-Like ECH-Associated Protein 1 ; Leukocytes, Mononuclear ; Chickens ; Hypertension, Pulmonary ; Inflammation ; Macrophages ; RNA, Messenger
Chemical Substances	Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1) ; Tumor Necrosis Factor-alpha ; NF-E2-Related Factor 2 ; Kelch-Like ECH-Associated Protein 1 ; RNA, Messenger
Language	English
Publishing date	2022-10-23
Publishing country	England
Document type	Journal Article
ZDB-ID	2041675-1
ISSN	1465-993X ; 1465-993X
ISSN (online)	1465-993X
ISSN	1465-993X
DOI	10.1186/s12931-022-02210-7
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