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1.
FASEB J ; 38(1): e23339, 2024 01.
Article in English | MEDLINE | ID: mdl-38069905

ABSTRACT

Being overweight exacerbates various metabolic diseases, necessitating the identification of target molecules for obesity control. In the current study, we investigated common physiological features related to metabolism in mice with low weight gain: (1) G protein-coupled receptor, family C, group 5, member B-knockout; (2) gastric inhibitory polypeptide receptor-knockout; and (3) Iroquois-related homeobox 3-knockout. Moreover, we explored genes involved in metabolism by analyzing differentially expressed genes (DEGs) between low-weight gain mice and the respective wild-type control mice. The common characteristics of the low-weight gain mice were low inguinal white adipose tissue (iWAT) and liver weight despite similar food intake along with lower blood leptin levels and high energy expenditure. The DEGs of iWAT, epididymal (gonadal) WAT, brown adipose tissue, muscle, liver, hypothalamus, and hippocampus common to these low-weight gain mice were designated as candidate genes associated with metabolism. One such gene tetraspanin 7 (Tspan7) from the iWAT was validated using knockout and overexpressing mouse models. Mice with low Tspan7 expression gained more weight, while those with high Tspan7 expression gained less weight, confirming the involvement of the Tspan7 gene in weight regulation. Collectively, these findings suggest that the candidate gene list generated in this study contains potential target molecules for obesity regulation. Further validation and additional data from low-weight gain mice will aid in understanding the molecular mechanisms associated with obesity.


Subject(s)
Adipose Tissue, Brown , Obesity , Mice , Animals , Obesity/genetics , Obesity/metabolism , Adipose Tissue, Brown/metabolism , Weight Gain/genetics , Adipose Tissue, White/metabolism , Energy Metabolism/genetics , Phenotype , Mice, Inbred C57BL , Diet, High-Fat , Mice, Knockout
2.
Leukemia ; 37(9): 1802-1811, 2023 09.
Article in English | MEDLINE | ID: mdl-37464069

ABSTRACT

SETBP1 is a potential epigenetic regulator whose hotspot mutations preventing proteasomal degradation are recurrently detected in myeloid malignancies with poor prognosis. It is believed that the mutant SETBP1 exerts amplified effects of wild-type SETBP1 rather than neomorphic functions. This indicates that dysregulated quantitative control of SETBP1 would result in the transformation of hematopoietic cells. However, little is known about the roles of endogenous SETBP1 in malignant and normal hematopoiesis. Thus, we integrated the analyses of primary AML and healthy samples, cancer cell lines, and a newly generated murine model, Vav1-iCre;Setbp1fl/fl. Despite the expression in long-term hematopoietic stem cells, SETBP1 depletion in normal hematopoiesis minimally alters self-renewal, differentiation, or reconstitution in vivo. Indeed, its loss does not profoundly alter transcription or chromatin accessibilities. Furthermore, although AML with high SETBP1 mRNA is associated with genetic and clinical characteristics for dismal outcomes, SETBP1 is dispensable for the development or maintenance of AML. Contrary to the evidence that SETBP1 mutations are restricted to myeloid malignancies, dependency on SETBP1 mRNA expression is not observed in AML. These unexpected results shed light on the unrecognized idea that a physiologically nonessential gene can act as an oncogene when the machinery of protein degradation is damaged.


Subject(s)
Hematopoiesis , Leukemia, Myeloid, Acute , Animals , Humans , Mice , Carrier Proteins/genetics , Cell Differentiation , Hematopoiesis/genetics , Hematopoietic Stem Cells/metabolism , Leukemia, Myeloid, Acute/pathology , Mutation , Nuclear Proteins/genetics
3.
J Autoimmun ; 127: 102794, 2022 02.
Article in English | MEDLINE | ID: mdl-35168003

ABSTRACT

Mutations in IFIH1 gene encoding viral RNA sensor MDA5 have been reported responsible for many interferonopathies, including Aicardi-Goutières syndrome (AGS) and monogenic lupus, however, the pathological link between IFIH1 mutations and various autoimmune symptoms remains unclear. Here, we generated transgenic mice expressing human MDA5 R779H mutant (R779H Tg), reported in AGS and monogenic lupus patient. Mice spontaneously developed myocarditis and nephritis with upregulation of type I IFNs in the major organs. R779H Tg Mavs-/- and R779H Tg Ifnar-/- showed no phenotypes, indicating direct MDA5-signaling pathway involvement. Rag-2 deficiency and bone marrow cells transfer from wild type to adult mice did not prevent myocarditis development, while mice with cardiomyocyte-specific expression of hMDA5 R779H showed cardiomegaly and high expression of inflammatory cytokines. Taken together, our study clarifies that type I IFNs production and chemokines from cardiomyocytes starts in neonatal period and is critical for the development of myocarditis. Activated lymphocytes and auto-antibodies exacerbate the pathogenesis but are dispensable for the onset.


Subject(s)
Interferon-Induced Helicase, IFIH1/genetics , Myocarditis , Nephritis , Animals , Autoimmune Diseases of the Nervous System/genetics , Humans , Interferon-Induced Helicase, IFIH1/metabolism , Mice , Mice, Transgenic , Mutation , Myocarditis/genetics , Nephritis/genetics
4.
Nat Commun ; 12(1): 2046, 2021 04 06.
Article in English | MEDLINE | ID: mdl-33824347

ABSTRACT

Bone formation represents a heritable trait regulated by many signals and complex mechanisms. Its abnormalities manifest themselves in various diseases, including sclerosing bone disorder (SBD). Exploration of genes that cause SBD has significantly improved our understanding of the mechanisms that regulate bone formation. Here, we discover a previously unknown type of SBD in four independent families caused by bi-allelic loss-of-function pathogenic variants in TMEM53, which encodes a nuclear envelope transmembrane protein. Tmem53-/- mice recapitulate the human skeletal phenotypes. Analyses of the molecular pathophysiology using the primary cells from the Tmem53-/- mice and the TMEM53 knock-out cell lines indicates that TMEM53 inhibits BMP signaling in osteoblast lineage cells by blocking cytoplasm-nucleus translocation of BMP2-activated Smad proteins. Pathogenic variants in the patients impair the TMEM53-mediated blocking effect, thus leading to overactivated BMP signaling that promotes bone formation and contributes to the SBD phenotype. Our results establish a previously unreported SBD entity (craniotubular dysplasia, Ikegawa type) and contribute to a better understanding of the regulation of BMP signaling and bone formation.


Subject(s)
Bone Morphogenetic Proteins/metabolism , Bone and Bones/pathology , Membrane Proteins/metabolism , Sclerosis/pathology , Signal Transduction , Smad Proteins/metabolism , Animals , Base Sequence , Cell Differentiation , Cell Nucleus/metabolism , Child , Child, Preschool , Female , Humans , Male , Membrane Proteins/genetics , Mice, Mutant Strains , Mutation/genetics , Osteoblasts/pathology , Pedigree , Phosphorylation , Skull/pathology , Young Adult
5.
Life Sci Alliance ; 2(2)2019 04.
Article in English | MEDLINE | ID: mdl-30936185

ABSTRACT

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies of human NK cells were confirmed in multiple organs of hIL-7 and hIL-15 double knockin (hIL-7xhIL-15 KI) NSG mice engrafted with human hematopoietic stem cells. hIL-7xhIL-15 KI NSG humanized mice provide a valuable in vivo model to investigate development and function of human NK cells.


Subject(s)
Cell Differentiation , Gene Knock-In Techniques , Interleukin-15/blood , Interleukin-15/genetics , Interleukin-7/blood , Interleukin-7/genetics , Killer Cells, Natural/physiology , Animals , CD56 Antigen/metabolism , Female , Fetal Blood/cytology , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Models, Animal , Thymus Gland/cytology , Transcriptome , Transplantation, Heterologous
6.
EBioMedicine ; 41: 584-596, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30772305

ABSTRACT

BACKGROUND: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence. METHODS: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34+CD38-CD45RA- haematopoietic stem/progenitor cells (HSPCs) into hIL-6 transgenic NOD/SCID/Il2rgKO (NSG) newborns, and compared GVHD progression with NSG newborns receiving CB CD34- cells mimicking acute GVHD. We characterised human immune cell subsets, target organ infiltration, T-cell repertoire (TCR) and transcriptome in the humanised mice. FINDINGS: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation. INTERPRETATION: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD.


Subject(s)
Graft vs Host Disease/immunology , Interleukin-6/genetics , Macrophages/immunology , T-Lymphocytes/immunology , Acute Disease , Animals , Animals, Newborn , Chronic Disease , Disease Models, Animal , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Humans , Interleukin Receptor Common gamma Subunit/deficiency , Interleukin Receptor Common gamma Subunit/genetics , Keratinocytes/cytology , Keratinocytes/metabolism , Macrophages/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Survival Rate , T-Lymphocytes/metabolism , Transcriptome
7.
Yakugaku Zasshi ; 138(5): 715-722, 2018.
Article in Japanese | MEDLINE | ID: mdl-29710016

ABSTRACT

 The importance of community-based care systems has increased due to the highly aging population and diversity of disease. To enhance the cooperation among healthcare professionals in community-based care systems, a two-day on-site training program for community pharmacists based on a multidisciplinary team approach was conducted at the Medical Science Hospital of Shiga University from April 2015 to March 2017. There were two professional courses in this training program: the palliative care course and nutrition support course. Both courses consisted of common pharmaceutical care training as follows: regional cooperation among healthcare professionals, pharmacist's clinical activities in the ward, pressure ulcer care, infection control, and aseptic technique for parenteral solutions. Each course was limited to 2 participants. A questionnaire was given to participants in the training program. Seventy-five pharmacists participated in the training and all of them answered the questionnaire. According to the questionnaire, 86% of participants felt that 2 days was an appropriate term for the training program. Positive answers regarding the content of each program and overall satisfaction were given by 100% and 99% of the participants, respectively. In the categorical classification of free comments regarding the expected change in pharmacy practice after the training, both "support for patients under nutritional treatment" and "cooperation with other medical staff" were answered by 24 participants. These results suggested that the 2-day on-site training for community pharmacists facilitated cooperation among healthcare professionals in the community.


Subject(s)
Community Health Services , Education, Pharmacy, Continuing/methods , Health Personnel , Intersectoral Collaboration , Pharmacists , Pharmacy Service, Hospital , Adult , Female , Humans , Interdisciplinary Communication , Male , Middle Aged , Patient Care Team , Surveys and Questionnaires , Young Adult
8.
J Clin Invest ; 126(6): 2064-76, 2016 06 01.
Article in English | MEDLINE | ID: mdl-27111231

ABSTRACT

Skin homeostasis is maintained by the continuous proliferation and differentiation of epidermal cells. The skin forms a strong but flexible barrier against microorganisms as well as physical and chemical insults; however, the physiological mechanisms that maintain this barrier are not fully understood. Here, we have described a mutant mouse that spontaneously develops pruritic dermatitis as the result of an initial defect in skin homeostasis that is followed by induction of a Th2-biased immune response. These mice harbor a mutation that results in a single aa substitution in the JAK1 tyrosine kinase that results in hyperactivation, thereby leading to skin serine protease overexpression and disruption of skin barrier function. Accordingly, treatment with an ointment to maintain normal skin barrier function protected mutant mice from dermatitis onset. Pharmacological inhibition of JAK1 also delayed disease onset. Together, these findings indicate that JAK1-mediated signaling cascades in skin regulate the expression of proteases associated with the maintenance of skin barrier function and demonstrate that perturbation of these pathways can lead to the development of spontaneous pruritic dermatitis.


Subject(s)
Dermatitis/etiology , Janus Kinase 1/genetics , Janus Kinase 1/metabolism , Mutant Proteins/genetics , Mutant Proteins/metabolism , Pruritus/etiology , Amino Acid Substitution , Animals , Dermatitis/enzymology , Dermatitis/genetics , Dermatitis, Atopic/enzymology , Dermatitis, Atopic/pathology , Disease Models, Animal , Enzyme Activation/genetics , Humans , Janus Kinase 1/antagonists & inhibitors , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains , Mutant Proteins/antagonists & inhibitors , Mutation, Missense , Pruritus/enzymology , Pruritus/genetics , Signal Transduction , Skin/enzymology , Skin/immunology , Skin/pathology
9.
Nat Cell Biol ; 18(2): 225-233, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26751286

ABSTRACT

Zygotic epigenetic reprogramming entails genome-wide DNA demethylation that is accompanied by Tet methylcytosine dioxygenase 3 (Tet3)-driven oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC; refs 1-4). Here we demonstrate using detailed immunofluorescence analysis and ultrasensitive LC-MS-based quantitative measurements that the initial loss of paternal 5mC does not require 5hmC formation. Small-molecule inhibition of Tet3 activity, as well as genetic ablation, impedes 5hmC accumulation in zygotes without affecting the early loss of paternal 5mC. Instead, 5hmC accumulation is dependent on the activity of zygotic Dnmt3a and Dnmt1, documenting a role for Tet3-driven hydroxylation in targeting de novo methylation activities present in the early embryo. Our data thus provide further insights into the dynamics of zygotic reprogramming, revealing an intricate interplay between DNA demethylation, de novo methylation and Tet3-driven hydroxylation.


Subject(s)
5-Methylcytosine/metabolism , Cellular Reprogramming , Cytosine/analogs & derivatives , DNA Methylation , Epigenesis, Genetic , Zygote/metabolism , Animals , Biomarkers/metabolism , Chromatography, Liquid , Cytosine/metabolism , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methyltransferase 3A , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Dioxygenases , Embryo Culture Techniques , Fertilization in Vitro , Fluorescent Antibody Technique , Gene Expression Regulation, Developmental , Kinetics , Mass Spectrometry , Mice , Mice, Knockout , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism
10.
PLoS Genet ; 9(11): e1003897, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24244179

ABSTRACT

Molecular mechanisms for the establishment of transcriptional memory are poorly understood. 5,6-dichloro-1-D-ribofuranosyl-benzimidazole (DRB) is a P-TEFb kinase inhibitor that artificially induces the poised RNA polymerase II (RNAPII), thereby manifesting intermediate steps for the establishment of transcriptional activation. Here, using genetics and DRB, we show that mammalian Absent, small, or homeotic discs 1-like (Ash1l), a member of the trithorax group proteins, methylates Lys36 of histone H3 to promote the establishment of Hox gene expression by counteracting Polycomb silencing. Importantly, we found that Ash1l-dependent Lys36 di-, tri-methylation of histone H3 in a coding region and exclusion of Polycomb group proteins occur independently of transcriptional elongation in embryonic stem (ES) cells, although both were previously thought to be consequences of transcription. Genome-wide analyses of histone H3 Lys36 methylation under DRB treatment have suggested that binding of the retinoic acid receptor (RAR) to a certain genomic region promotes trimethylation in the RAR-associated gene independent of its ongoing transcription. Moreover, DRB treatment unveils a parallel response between Lys36 methylation of histone H3 and occupancy of either Tip60 or Mof in a region-dependent manner. We also found that Brg1 is another key player involved in the response. Our results uncover a novel regulatory cascade orchestrated by Ash1l with RAR and provide insights into mechanisms underlying the establishment of the transcriptional activation that counteracts Polycomb silencing.


Subject(s)
DNA-Binding Proteins/metabolism , Histones/metabolism , Polycomb-Group Proteins/genetics , Transcription Factors/metabolism , Transcription, Genetic , Transcriptional Elongation Factors/genetics , Animals , Chromatin/genetics , DNA-Binding Proteins/genetics , Dichlororibofuranosylbenzimidazole/pharmacology , Drosophila Proteins/metabolism , Drosophila melanogaster , Gene Silencing , Histone Acetyltransferases/metabolism , Histone-Lysine N-Methyltransferase , Histones/genetics , Humans , Lysine/genetics , Methylation , Nuclear Proteins/metabolism , Polycomb-Group Proteins/metabolism , Positive Transcriptional Elongation Factor B/antagonists & inhibitors , Positive Transcriptional Elongation Factor B/metabolism , RNA Polymerase II/genetics , Transcription Factors/genetics , Transcriptional Elongation Factors/metabolism
11.
Genesis ; 49(1): 2-9, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21254332

ABSTRACT

Irxl1 (Iroquois-related homeobox like-1) is a newly identified three amino-acid loop extension (TALE) homeobox gene, which is expressed in various mesoderm-derived tissues, particularly in the progenitors of the musculoskeletal system. To analyze the roles of Irxl1 during embryonic development, we generated mice carrying a null allele of Irxl1. Mice homozygous for the targeted allele were viable, fertile, and showed reduced tendon differentiation. Skeletal morphology and skeletal muscle weight in Irxl1-knockout mice appeared normal. Expression patterns of several marker genes for cartilage, tendon, and muscle progenitors in homozygous mutant embryos were unchanged. These results suggest that Irxl1 is required for the tendon differentiation but dispensable for the patterning of the musculoskeletal system in development.


Subject(s)
Homeodomain Proteins/genetics , Tendons/embryology , Animals , Body Patterning/genetics , Mice , Mice, Knockout , Musculoskeletal Development/genetics , Musculoskeletal System/anatomy & histology , Musculoskeletal System/embryology , Recombination, Genetic , Repressor Proteins/genetics
12.
J Clin Invest ; 120(7): 2610-8, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20516640

ABSTRACT

NKT cells demonstrate antitumor activity when activated to produce Th1 cytokines by DCs loaded with alpha-galactosylceramide, the prototypic NKT cell-activating glycolipid antigen. However, most patients do not have sufficient numbers of NKT cells to induce an effective immune response in this context, indicating a need for a source of NKT cells that could be used to supplement the endogenous cell population. Induced pluripotent stem cells (iPSCs) hold tremendous potential for cell-replacement therapy, but whether it is possible to generate functionally competent NKT cells from iPSCs has not been rigorously assessed. In this study, we successfully derived iPSCs both from embryonic fibroblasts from mice harboring functional NKT cell-specific rearranged T cell receptor loci in the germline and from splenic NKT cells from WT adult mice. These iPSCs could be differentiated into NKT cells in vitro and secreted large amounts of the Th1 cytokine IFN-gamma. Importantly, iPSC-derived NKT cells recapitulated the known adjuvant effects of natural NKT cells and suppressed tumor growth in vivo. These studies demonstrate the feasibility of expanding functionally competent NKT cells via an iPSC phase, an approach that may be adapted for NKT cell-targeted therapy in humans.


Subject(s)
Natural Killer T-Cells/immunology , Animals , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cytokines/immunology , Cytokines/pharmacology , Galactosylceramides/immunology , Galactosylceramides/pharmacology , Glycolipids/immunology , Glycolipids/pharmacology , Induced Pluripotent Stem Cells , Mice , Neoplasms/immunology , Receptors, Antigen, T-Cell/immunology , Spleen/drug effects , Spleen/immunology
13.
Genesis ; 48(5): 295-302, 2010 May.
Article in English | MEDLINE | ID: mdl-20162674

ABSTRACT

To study the expression/function of Tbx10, a T-box gene, Tbx10(LacZ/+) mice were established by replacing the T-box coding region with a LacZ gene. X-gal staining showed that LacZ(+) cells were localized to two-cell populations in rhombomere 4 and rhombomere 6. No significant differences in the locations of LacZ(+) cells were found between Tbx10(LacZ/+) and Tbx10(LacZ/LacZ) mice, and the Tbx10(LacZ/LacZ) mice were viable and fertile. We found that the LacZ(+) cells are present in both embryonic and adult mice. Histological studies suggest that the rhombomere 4-derived LacZ(+) cells are a subpopulation of the ventral interneurons in the pons.


Subject(s)
Gene Expression Profiling , Gene Expression Regulation, Developmental , Rhombencephalon/metabolism , T-Box Domain Proteins/genetics , Alleles , Animals , Embryo, Mammalian/cytology , Embryo, Mammalian/embryology , Embryo, Mammalian/metabolism , Female , Immunohistochemistry , In Situ Hybridization , Interneurons/cytology , Interneurons/metabolism , Lac Operon/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Transgenic , Mutation , Pons/cytology , Pons/embryology , Pons/metabolism , Rhombencephalon/cytology , Rhombencephalon/embryology , T-Box Domain Proteins/metabolism , beta-Galactosidase/metabolism
14.
Mol Cell Biol ; 29(18): 5128-35, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19620281

ABSTRACT

A critical step during intrathymic T-cell development is the transition of CD4(+) CD8(+) double-positive (DP) cells to the major histocompatibility complex class I (MHC-I)-restricted CD4(-) CD8(+) and MHC-II-restricted CD4(+) CD8(-) single-positive (SP) cell stage. Here, we identify a novel gene that is essential for this process. Through the T-cell phenotype-based screening of N-ethyl-N-nitrosourea (ENU)-induced mutant mice, we established a mouse line in which numbers of CD4 and CD8 SP thymocytes as well as peripheral CD4 and CD8 T cells were dramatically reduced. Using linkage analysis and DNA sequencing, we identified a missense point mutation in a gene, E430004N04Rik (also known as themis), that does not belong to any known gene family. This orphan gene is expressed specifically in DP and SP thymocytes and peripheral T cells, whereas in mutant thymocytes the levels of protein encoded by this gene were drastically reduced. We generated E430004N04Rik-deficient mice, and their phenotype was virtually identical to that of the ENU mutant mice, thereby confirming that this gene is essential for the development of SP thymocytes.


Subject(s)
Genes, Essential , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Amino Acid Sequence , Animals , Base Sequence , Chromosome Mapping , Ethylnitrosourea , Genome/genetics , Mice , Mice, Mutant Strains , Molecular Sequence Data , Mutation, Missense/genetics , Phenotype , Polymorphism, Single Nucleotide/genetics , Proteins/chemistry , Proteins/genetics , Proteins/metabolism , Sequence Homology, Amino Acid , Stromal Cells/cytology , Stromal Cells/metabolism
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