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1.
Nat Immunol ; 24(8): 1358-1369, 2023 08.
Article in English | MEDLINE | ID: mdl-37365386

ABSTRACT

Following infection or vaccination, activated B cells at extrafollicular sites or within germinal centers (GCs) undergo vigorous clonal proliferation. Proliferating lymphocytes have been shown to undertake lactate dehydrogenase A (LDHA)-dependent aerobic glycolysis; however, the specific role of this metabolic pathway in a B cell transitioning from a naïve to a highly proliferative, activated state remains poorly defined. Here, we deleted LDHA in a stage-specific and cell-specific manner. We find that ablation of LDHA in a naïve B cell did not profoundly affect its ability to undergo a bacterial lipopolysaccharide-induced extrafollicular B cell response. On the other hand, LDHA-deleted naïve B cells had a severe defect in their capacities to form GCs and mount GC-dependent antibody responses. In addition, loss of LDHA in T cells severely compromised B cell-dependent immune responses. Strikingly, when LDHA was deleted in activated, as opposed to naïve, B cells, there were only minimal effects on the GC reaction and in the generation of high-affinity antibodies. These findings strongly suggest that naïve and activated B cells have distinct metabolic requirements that are further regulated by niche and cellular interactions.


Subject(s)
B-Lymphocytes , Germinal Center , T-Lymphocytes , Lymphocyte Activation , Cell Communication
2.
Immunity ; 53(5): 952-970.e11, 2020 11 17.
Article in English | MEDLINE | ID: mdl-33098766

ABSTRACT

Precise targeting of activation-induced cytidine deaminase (AID) to immunoglobulin (Ig) loci promotes antibody class switch recombination (CSR) and somatic hypermutation (SHM), whereas AID targeting of non-Ig loci can generate oncogenic DNA lesions. Here, we examined the contribution of G-quadruplex (G4) nucleic acid structures to AID targeting in vivo. Mice bearing a mutation in Aicda (AIDG133V) that disrupts AID-G4 binding modeled the pathology of hyper-IgM syndrome patients with an orthologous mutation, lacked CSR and SHM, and had broad defects in genome-wide AIDG133V chromatin localization. Genome-wide analyses also revealed that wild-type AID localized to MHCII genes, and AID expression correlated with decreased MHCII expression in germinal center B cells and diffuse large B cell lymphoma. Our findings indicate a crucial role for G4 binding in AID targeting and suggest that AID activity may extend beyond Ig loci to regulate the expression of genes relevant to the physiology and pathology of activated B cells.


Subject(s)
Chromatin/genetics , Chromatin/metabolism , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , G-Quadruplexes , Hyper-IgM Immunodeficiency Syndrome/etiology , Hyper-IgM Immunodeficiency Syndrome/metabolism , Mutation , Animals , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Computational Biology/methods , Disease Models, Animal , Disease Susceptibility , Enzyme Activation , Fluorescent Antibody Technique , Gene Expression Profiling , Genome-Wide Association Study , Germinal Center/immunology , Germinal Center/metabolism , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Hyper-IgM Immunodeficiency Syndrome/diagnosis , Immunoglobulin Class Switching/genetics , Immunoglobulin Class Switching/immunology , Immunophenotyping , Lymphocyte Activation/genetics , Lymphoma, Large B-Cell, Diffuse/etiology , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Mice , Mice, Transgenic
3.
Mol Cell ; 73(3): 458-473.e7, 2019 02 07.
Article in English | MEDLINE | ID: mdl-30581148

ABSTRACT

Cholesterol is highly enriched at the plasma membrane (PM), and lipid transfer proteins may deliver cholesterol to the PM in a nonvesicular manner. Here, through a mini-screen, we identified the oxysterol binding protein (OSBP)-related protein 2 (ORP2) as a novel mediator of selective cholesterol delivery to the PM. Interestingly, ORP2-mediated enrichment of PM cholesterol was coupled with the removal of phosphatidylinositol 4, 5-bisphosphate (PI(4,5)P2) from the PM. ORP2 overexpression or deficiency impacted the levels of PM cholesterol and PI(4,5)P2, and ORP2 efficiently transferred both cholesterol and PI(4,5)P2in vitro. We determined the structure of ORP2 in complex with PI(4,5)P2 at 2.7 Å resolution. ORP2 formed a stable tetramer in the presence of PI(4,5)P2, and tetramerization was required for ORP2 to transfer PI(4,5)P2. Our results identify a novel pathway for cholesterol delivery to the PM and establish ORP2 as a key regulator of both cholesterol and PI(4,5)P2 of the PM.


Subject(s)
Cell Membrane/metabolism , Cholesterol/metabolism , Hepatocytes/metabolism , Phosphatidylinositol 4,5-Diphosphate/metabolism , Receptors, Steroid/metabolism , Biological Transport , Cell Line, Tumor , HEK293 Cells , Humans , Models, Molecular , Protein Multimerization , Protein Structure, Quaternary , Receptors, Steroid/chemistry , Receptors, Steroid/genetics , Structure-Activity Relationship
4.
EMBO J ; 41(2): e108591, 2022 12 17.
Article in English | MEDLINE | ID: mdl-34842295

ABSTRACT

It is still unclear why pathological amyloid deposition initiates in specific brain regions or why some cells or tissues are more susceptible than others. Amyloid deposition is determined by the self-assembly of short protein segments called aggregation-prone regions (APRs) that favour cross-ß structure. Here, we investigated whether Aß amyloid assembly can be modified by heterotypic interactions between Aß APRs and short homologous segments in otherwise unrelated human proteins. Mining existing proteomics data of Aß plaques from AD patients revealed an enrichment in proteins that harbour such homologous sequences to the Aß APRs, suggesting heterotypic amyloid interactions may occur in patients. We identified homologous APRs from such proteins and show that they can modify Aß assembly kinetics, fibril morphology and deposition pattern in vitro. Moreover, we found three of these proteins upon transient expression in an Aß reporter cell line promote Aß amyloid aggregation. Strikingly, we did not find a bias towards heterotypic interactions in plaques from AD mouse models where Aß self-aggregation is observed. Based on these data, we propose that heterotypic APR interactions may play a hitherto unrealized role in amyloid-deposition diseases.


Subject(s)
Amyloid beta-Peptides/metabolism , Protein Interaction Maps , Proteome/metabolism , Amyloid beta-Peptides/chemistry , HEK293 Cells , Humans , Protein Binding , Protein Multimerization , Proteome/chemistry
5.
Brief Bioinform ; 24(6)2023 09 22.
Article in English | MEDLINE | ID: mdl-37833844

ABSTRACT

Considering that cancer is resulting from the comutation of several essential genes of individual patients, researchers have begun to focus on identifying personalized edge-network biomarkers (PEBs) using personalized edge-network analysis for clinical practice. However, most of existing methods ignored the optimization of PEBs when multimodal biomarkers exist in multi-purpose early disease prediction (MPEDP). To solve this problem, this study proposes a novel model (MMPDENB-RBM) that combines personalized dynamic edge-network biomarkers (PDENB) theory, multimodal optimization strategy and latent space search scheme to identify biomarkers with different configurations of PDENB modules (i.e. to effectively identify multimodal PDENBs). The application to the three largest cancer omics datasets from The Cancer Genome Atlas database (i.e. breast invasive carcinoma, lung squamous cell carcinoma and lung adenocarcinoma) showed that the MMPDENB-RBM model could more effectively predict critical cancer state compared with other advanced methods. And, our model had better convergence, diversity and multimodal property as well as effective optimization ability compared with the other state-of-art methods. Particularly, multimodal PDENBs identified were more enriched with different functional biomarkers simultaneously, such as tissue-specific synthetic lethality edge-biomarkers including cancer driver genes and disease marker genes. Importantly, as our aim, these multimodal biomarkers can perform diverse biological and biomedical significances for drug target screen, survival risk assessment and novel biomedical sight as the expected multi-purpose of personalized early disease prediction. In summary, the present study provides multimodal property of PDENBs, especially the therapeutic biomarkers with more biological significances, which can help with MPEDP of individual cancer patients.


Subject(s)
Adenocarcinoma of Lung , Breast Neoplasms , Lung Neoplasms , Humans , Female , Biomarkers , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Oncogenes , Adenocarcinoma of Lung/genetics , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics
6.
J Pathol ; 262(4): 517-528, 2024 04.
Article in English | MEDLINE | ID: mdl-38361487

ABSTRACT

This study aimed to provide more information for prognostic stratification for patients through an analysis of the T-cell spatial landscape. It involved analyzing stained tissue sections of 80 patients with stage III lung adenocarcinoma (LUAD) using multiplex immunofluorescence and exploring the spatial landscape of T cells and their relationship with prognosis in the center of the tumor (CT) and invasive margin (IM). In this study, multivariate regression suggested that the relative clustering of CT CD4+ conventional T cell (Tconv) to inducible Treg (iTreg), natural regulatory T cell (nTreg) to Tconv, terminal CD8+ T cell (tCD8) to helper T cell (Th), and IM Treg to tCD8 and the relative dispersion of CT nTreg to iTreg, IM nTreg to nTreg were independent risk factors for DFS. Finally, we constructed a spatial immunological score named the GT score, which had stronger prognostic correlation than IMMUNOSCORE® based on CD3/CD8 cell densities. The spatial layout of T cells in the tumor microenvironment and the proposed GT score can reflect the prognosis of patients with stage III LUAD more effectively than T-cell density. The exploration of the T-cell spatial landscape may suggest potential cell-cell interactions and therapeutic targets and better guide clinical decision-making. © 2024 The Pathological Society of Great Britain and Ireland.


Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , CD8-Positive T-Lymphocytes , T-Lymphocytes, Regulatory , Prognosis , Adenocarcinoma of Lung/pathology , United Kingdom , Tumor Microenvironment , Lung Neoplasms/pathology
7.
Drug Resist Updat ; 76: 101115, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39002266

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, notably resistant to existing therapies. Current research indicates that PDAC patients deficient in homologous recombination (HR) benefit from platinum-based treatments and poly-ADP-ribose polymerase inhibitors (PARPi). However, the effectiveness of PARPi in HR-deficient (HRD) PDAC is suboptimal, and significant challenges remain in fully understanding the distinct characteristics and implications of HRD-associated PDAC. We analyzed 16 PDAC patient-derived tissues, categorized by their homologous recombination deficiency (HRD) scores, and performed high-plex immunofluorescence analysis to define 20 cell phenotypes, thereby generating an in-situ PDAC tumor-immune landscape. Spatial phenotypic-transcriptomic profiling guided by regions-of-interest (ROIs) identified a crucial regulatory mechanism through localized tumor-adjacent macrophages, potentially in an HRD-dependent manner. Cellular neighborhood (CN) analysis further demonstrated the existence of macrophage-associated high-ordered cellular functional units in spatial contexts. Using our multi-omics spatial profiling strategy, we uncovered a dynamic macrophage-mediated regulatory axis linking HRD status with SIGLEC10 and CD52. These findings demonstrate the potential of targeting CD52 in combination with PARPi as a therapeutic intervention for PDAC.


Subject(s)
Carcinoma, Pancreatic Ductal , Homologous Recombination , Macrophages , Pancreatic Neoplasms , Humans , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Macrophages/immunology , Macrophages/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Tumor Microenvironment/immunology
8.
Genomics ; 116(5): 110889, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38901654

ABSTRACT

Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.

9.
Plant J ; 114(6): 1405-1424, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36948889

ABSTRACT

Protein lysine acetylation is an important post-translational modification mechanism involved in cellular regulation in eukaryotes. Calmodulin (CaM) is a ubiquitous Ca2+ sensor in eukaryotes and is crucial for plant immunity, but it is so far unclear whether acetylation is involved in CaM-mediated plant immunity. Here, we found that GhCaM7 is acetylated upon Verticillium dahliae (V. dahliae) infection and a positive regulator of V. dahliae resistance. Overexpressing GhCaM7 in cotton and Arabidopsis enhances V. dahliae resistance and knocking-down GhCaM7 makes cotton more susceptible to V. dahliae. Transgenic Arabidopsis plants overexpressing GhCaM7 with mutation at the acetylation site are more susceptible to V. dahliae than transgenics overexpressing the wild-type GhCaM7, implying the importance of the acetylated GhCaM7 in response to V. dahliae infection. Yeast two-hybrid, bimolecular fluorescent complementation, luciferase complementation imaging, and coimmunoprecipitation assays demonstrated interaction between GhCaM7 and an osmotin protein GhOSM34 that was shown to have a positive role in V. dahliae resistance. GhCaM7 and GhOSM34 are co-localized in the cell membrane. Upon V. dahliae infection, the Ca2+ content reduces almost instantly in plants with downregulated GhCaM7 or GhOSM34. Down regulating GhOSM34 enhances accumulation of Na+ and increases cell osmotic pressure. Comparative transcriptomic analyses between cotton plants with an increased or reduced expression level of GhCaM7 and wild-type plants indicate the involvement of jasmonic acid signaling pathways and reactive oxygen species in GhCaM7-enabled disease resistance. Together, these results demonstrate the involvement of CaM protein in the interaction between cotton and V. dahliae, and more importantly, the involvement of the acetylated CaM in the interaction.


Subject(s)
Arabidopsis , Ascomycota , Verticillium , Gossypium/genetics , Gossypium/metabolism , Arabidopsis/genetics , Arabidopsis/metabolism , Plant Proteins/metabolism , Acetylation , Verticillium/physiology , Disease Resistance/genetics , Ascomycota/genetics , Calmodulin/genetics , Calmodulin/metabolism , Protein Processing, Post-Translational , Plants, Genetically Modified/metabolism , Plant Diseases , Gene Expression Regulation, Plant
10.
Int J Cancer ; 154(3): 530-537, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-37815300

ABSTRACT

Several observational studies have reported an association between obesity and primary liver cancer (PLC), while the causality behind this association and the comparison of the risk effects of different obesity indicators on PLC remain unclear. In this study, we performed two-sample Mendelian randomization (MR) analyses to assess the associations of genetically determined liver fat, visceral adipose tissue (VAT), and body mass index (BMI) with the risk of PLC. The summary statistics of exposures were obtained from two genome-wide association studies (GWASs) based on the UK Biobank (UKB) imaging cohort and the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. GWAS summary statistics for PLC were obtained from FinnGen consortium R7 release data, including 304 PLC cases and 218 488 controls. Inverse-variance weighted (IVW) was used as the primary analysis, and a series of sensitivity analyses were performed to further verify the robustness of these findings. IVW analysis highlighted a significant association of genetically determined liver fat (OR per SD increase: 7.14; 95% CI: 5.10-9.99; P = 2.35E-30) and VAT (OR per SD increase: 5.70; 95% CI: 1.32-24.72; P = .020) with PLC but not of BMI with PLC. The findings were further confirmed by a series of MR methods. No evidence of horizontal pleiotropy between these associations existed. Our study suggested that genetically determined liver fat and VAT rather than BMI were associated with an increased risk of PLC, which suggested that visceral fat distribution is more predictive of the clinical risk of PLC than common in vitro measures.


Subject(s)
Genome-Wide Association Study , Liver Neoplasms , Adult , Humans , Mendelian Randomization Analysis , Obesity/complications , Obesity/genetics , Liver Neoplasms/etiology , Liver Neoplasms/genetics , Polymorphism, Single Nucleotide
11.
Funct Integr Genomics ; 24(1): 15, 2024 Jan 19.
Article in English | MEDLINE | ID: mdl-38240925

ABSTRACT

Chronic psoriasis is a kind of immune-mediated skin illness and the underlying molecular mechanisms of pathogenesis remain incompletely understood. Here, we used small RNA microarray assays to scan the differential expressed RNAs in psoriasis patient samples. The downstream miRNAs and its targets were predicted using bioinformatics analysis from online bases and confirmed using fluorescence in situ hybridization and dual­luciferase report gene assay. Cell ability of proliferation and migration were detected using CCK-8 and transwell assays. The results showed that a new snoRNA Snora73 was upregulated in psoriasis patient samples. Overexpression of Snora73 significantly increased psoriasis cells viability and migration, while knockdown of Snora73 got the opposite results. Mechanistically, our results showed that Snora73 acted as a sponge for miR-3074-5p and PBX1 is a direct target of miR-3074-5p in psoriasis cells. Furthermore, miR-3074-5p suppressed psoriasis cell proliferation and migration, while PBX1 promoted cell proliferation and migration in psoriasis. Collectively, these findings reveal a crucial role of Snora73 in progression of psoriasis through miR-3074-5p/PBX1 signaling pathway and suggest a potential therapeutic strategy.


Subject(s)
MicroRNAs , Pre-B-Cell Leukemia Transcription Factor 1 , Psoriasis , RNA, Long Noncoding , RNA, Small Nucleolar , Humans , Cell Line, Tumor , Cell Proliferation/genetics , In Situ Hybridization, Fluorescence , MicroRNAs/genetics , Psoriasis/genetics , RNA, Long Noncoding/genetics , RNA, Small Nucleolar/genetics , Pre-B-Cell Leukemia Transcription Factor 1/genetics
12.
J Neuroinflammation ; 21(1): 29, 2024 Jan 22.
Article in English | MEDLINE | ID: mdl-38246987

ABSTRACT

Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3'UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Exosomes , MicroRNAs , Myelin Sheath , Animals , Mice , Exosomes/metabolism , Microglia/metabolism , MicroRNAs/genetics
13.
Brief Bioinform ; 23(5)2022 09 20.
Article in English | MEDLINE | ID: mdl-35858208

ABSTRACT

Finding personalized biomarkers for disease prediction of patients with cancer remains a massive challenge in precision medicine. Most methods focus on one subnetwork or module as a network biomarker; however, this ignores the early warning capabilities of other modules with different configurations of biomarkers (i.e. multi-modal personalized biomarkers). Identifying such modules would not only predict disease but also provide effective therapeutic drug target information for individual patients. To solve this problem, we developed a novel model (denoted multi-modal personalized dynamic network biomarkers (MMPDNB)) based on a multi-modal optimization mechanism and personalized dynamic network biomarker (PDNB) theory, which can provide multiple modules of personalized biomarkers and unveil their multi-modal properties. Using the genomics data of patients with breast or lung cancer from The Cancer Genome Atlas database, we validated the effectiveness of the MMPDNB model. The experimental results showed that compared with other advanced methods, MMPDNB can more effectively predict the critical state with the highest early warning signal score during cancer development. Furthermore, MMPDNB more significantly identified PDNBs containing driver and biomarker genes specific to cancer tissues. More importantly, we validated the biological significance of multi-modal PDNBs, which could provide effective drug targets of individual patients as well as markers for predicting early warning signals of the critical disease state. In conclusion, multi-modal optimization is an effective method to identify PDNBs and offers a new perspective for understanding tumor heterogeneity in cancer precision medicine.


Subject(s)
Genomics , Lung Neoplasms , Biomarkers , Genomics/methods , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Precision Medicine/methods
14.
Biochem Soc Trans ; 52(2): 761-771, 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38600027

ABSTRACT

Recent developments in atomic force microscopy (AFM) image analysis have made three-dimensional (3D) structural reconstruction of individual particles observed on 2D AFM height images a reality. Here, we review the emerging contact point reconstruction AFM (CPR-AFM) methodology and its application in 3D reconstruction of individual helical amyloid filaments in the context of the challenges presented by the structural analysis of highly polymorphous and heterogeneous amyloid protein structures. How individual particle-level structural analysis can contribute to resolving the amyloid polymorph structure-function relationships, the environmental triggers leading to protein misfolding and aggregation into amyloid species, the influences by the conditions or minor fluctuations in the initial monomeric protein structure on the speed of amyloid fibril formation, and the extent of the different types of amyloid species that can be formed, are discussed. Future perspectives in the capabilities of AFM-based 3D structural reconstruction methodology exploiting synergies with other recent AFM technology advances are also discussed to highlight the potential of AFM as an emergent general, accessible and multimodal structural biology tool for the analysis of individual biomolecules.


Subject(s)
Amyloid , Imaging, Three-Dimensional , Microscopy, Atomic Force , Microscopy, Atomic Force/methods , Imaging, Three-Dimensional/methods , Humans , Amyloid/chemistry , Amyloid/metabolism , Amyloidogenic Proteins/chemistry , Amyloidogenic Proteins/metabolism , Protein Conformation , Protein Folding
15.
Plant Physiol ; 193(2): 1527-1546, 2023 09 22.
Article in English | MEDLINE | ID: mdl-37432453

ABSTRACT

In the Rhizobium-Legume symbiosis, the nodulation outer protein P (NopP) effector is one of the key regulators for rhizobial infection and nodule organogenesis. However, the molecular mechanism through which host legume plants sense NopP remains largely unknown. Here, we constructed an nopP deletion mutant of Mesorhizobium huakuii and found that nopP negatively regulates nodulation on Chinese milk vetch (Astragalus sinicus). Screening for NopP interacting proteins in host plants using the yeast 2-hybrid system identified NopP interacting protein 43 (AsNIP43), which encodes a G-type receptor-like kinase (LecRLK). The B-lectin domain at the N terminus of AsNIP43 was essential in mediating its interaction with NopP, which was confirmed in vitro and in vivo. Subcellular localization, co-localization, and gene expression analyses showed that AsNIP43 and NopP function tightly associated with earlier infection events. RNA interference (RNAi) knockdown of AsNIP43 expression by hairy root transformation led to decreased nodule formation. AsNIP43 plays a positive role in symbiosis, which was further verified in the model legume Medicago truncatula. Transcriptome analysis indicated that MtRLK (a homolog of AsNIP43 in M. truncatula) may function to affect defense gene expression and thus to regulate early nodulation. Taken together, we show that LecRLK AsNIP43 is a legume host target that interacts with rhizobia effector NopP is essential for rhizobial infection and nodulation.


Subject(s)
Astragalus Plant , Medicago truncatula , Rhizobium , Symbiosis/genetics , Plant Root Nodulation/genetics , Phenotype , Carrier Proteins/genetics , Medicago truncatula/genetics , Rhizobium/physiology
16.
Plant Physiol ; 192(4): 2737-2755, 2023 08 03.
Article in English | MEDLINE | ID: mdl-37086480

ABSTRACT

Magnesium chelatase (MgCh) catalyzes the insertion of magnesium into protoporphyrin IX, a vital step in chlorophyll (Chl) biogenesis. The enzyme consists of 3 subunits, MgCh I subunit (CHLI), MgCh D subunit (CHLD), and MgCh H subunit (CHLH). The CHLI subunit is an ATPase that mediates catalysis. Previous studies on CHLI have mainly focused on model plant species, and its functions in other species have not been well described, especially with regard to leaf coloration and metabolism. In this study, we identified and characterized a CHLI mutant in strawberry species Fragaria pentaphylla. The mutant, noted as p240, exhibits yellow-green leaves and a low Chl level. RNA-Seq identified a mutation in the 186th amino acid of the CHLI subunit, a base conserved in most photosynthetic organisms. Transient transformation of wild-type CHLI into p240 leaves complemented the mutant phenotype. Further mutants generated from RNA-interference (RNAi) and CRISPR/Cas9 gene editing recapitulated the mutant phenotype. Notably, heterozygous chli mutants accumulated more Chl under low light conditions compared with high light conditions. Metabolite analysis of null mutants under high light conditions revealed substantial changes in both nitrogen and carbon metabolism. Further analysis indicated that mutation in Glu186 of CHLI does not affect its subcellular localization nor the interaction between CHLI and CHLD. However, intramolecular interactions were impaired, leading to reduced ATPase and MgCh activity. These findings demonstrate that Glu186 plays a key role in enzyme function, affecting leaf coloration via the formation of the hexameric ring itself, and that manipulation of CHLI may be a means to improve strawberry plant fitness and photosynthetic efficiency under low light conditions.


Subject(s)
Fragaria , Lyases , Point Mutation , Fragaria/genetics , Fragaria/metabolism , Lyases/genetics , Lyases/metabolism , Mutation/genetics , Adenosine Triphosphatases/metabolism , Plant Leaves/genetics , Plant Leaves/metabolism , Chlorophyll/metabolism
17.
Cardiovasc Diabetol ; 23(1): 293, 2024 Aug 08.
Article in English | MEDLINE | ID: mdl-39118078

ABSTRACT

BACKGROUND: The adverse prognostic impact of diabetes on hypertrophic cardiomyopathy (HCM) is poorly understood. We sought to explore the underlying mechanisms in terms of structural and functional remodelling in HCM patients with coexisting diabetes (HCM-DM). METHODS: A total of 45 HCM-DM patients were retrospectively included. Isolated HCM controls (HCM patients without diabetes) were matched to HCM-DM patients in terms of maximal wall thickness, age, and gender distribution. Left ventricular (LV) and atrial (LA) performance were evaluated using cardiac magnetic resonance feature tracking strain analyses. The associations between diabetes and LV/LA impairment were investigated by univariable and multivariable linear regression. RESULTS: Compared with the isolated HCM controls, the HCM-DM patients had smaller end-diastolic volume and stroke volume, lower ejection fraction, larger mass/volume ratio and impaired strains in all three directions (all P < 0.05). In terms of the LA parameters, HCM-DM patients presented impaired LA reservoir and conduit strain/strain rate (all P < 0.05). Among all HCM patients, comorbidity with diabetes was independently associated with a low LV ejection fraction (ß = - 6.05, P < 0.001) and impaired global longitudinal strain (ß = 1.40, P = 0.007). Moreover, compared with the isolated HCM controls, HCM-DM patients presented with more myocardial fibrosis according to late gadolinium enhancement, which was an independent predictor of impaired LV global radial strain (ß = - 45.81, P = 0.008), LV global circumferential strain (ß = 18.25, P = 0.003), LA reservoir strain (ß = - 59.20, P < 0.001) and strain rate (ß = - 2.90, P = 0.002). CONCLUSIONS: Diabetes has adverse effects on LV and LA function in HCM patients, which may be important contributors to severe manifestations and outcomes in those patients. The present study strengthened the evidence of the prevention and management of diabetes in HCM patients.


Subject(s)
Atrial Function, Left , Cardiomyopathy, Hypertrophic , Diabetes Mellitus , Magnetic Resonance Imaging, Cine , Predictive Value of Tests , Stroke Volume , Ventricular Function, Left , Ventricular Remodeling , Humans , Male , Female , Middle Aged , Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/physiopathology , Cardiomyopathy, Hypertrophic/complications , Retrospective Studies , Aged , Diabetes Mellitus/epidemiology , Diabetes Mellitus/physiopathology , Diabetes Mellitus/diagnosis , Risk Factors , Adult , Prognosis , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/etiology , Comorbidity , Atrial Remodeling
18.
Cardiovasc Diabetol ; 23(1): 294, 2024 Aug 08.
Article in English | MEDLINE | ID: mdl-39118075

ABSTRACT

BACKGROUND: Patients with concomitant type 2 diabetes mellitus (T2DM) and aortic regurgitation (AR) can present with right ventricular (RV) dysfunction. The current study aimed to evaluate the impact of AR on RV impairment and the importance of ventricular interdependence using cardiac magnetic resonance feature tracking (CMR­FT) in patients with T2DM. METHODS: This study included 229 patients with T2DM (AR-), 88 patients with T2DM (AR+), and 122 healthy controls. The biventricular global radial strain (GRS), global circumferential strain (GCS), and global longitudinal peak strain (GLS) were calculated with CMR­FT and compared among the healthy control, T2DM (AR-), and T2DM (AR+) groups. The RV regional strains at the basal, mid, and apical cavities between the T2DM (AR+) group and subgroups with different AR degrees were compared. Backward stepwise multivariate linear regression analyses were performed to determine the effects of AR and left ventricular (LV) strains on RV strains. RESULTS: The RV GLS, LV GRS, LV GCS, LV GLS, interventricular septal (IVS) GRS and IVS GCS were decreased gradually from the controls through the T2DM (AR-) group to the T2DM (AR+) group. The IVS GLS of the T2DM (AR-) and T2DM (AR+) groups was lower than that of the control group. AR was independently associated with LV GRS, LV GCS, LV GLS, RV GCS, and RV GLS. If AR and LV GLSs were included in the regression analyses, AR and LV GLS were independently associated with RV GLS. CONCLUSION: AR can exacerbate RV dysfunction in patients with T2DM, which may be associated with the superimposed strain injury of the left ventricle and interventricular septum. The RV longitudinal and circumferential strains are important indicators of cardiac injury in T2DM and AR. The unfavorable LV-RV interdependence supports that while focusing on improving LV function, RV dysfunction should be monitored and treated in order to slow the progression of the disease and the onset of adverse outcomes.


Subject(s)
Aortic Valve Insufficiency , Diabetes Mellitus, Type 2 , Magnetic Resonance Imaging, Cine , Predictive Value of Tests , Ventricular Dysfunction, Right , Ventricular Function, Left , Ventricular Function, Right , Humans , Male , Aortic Valve Insufficiency/physiopathology , Aortic Valve Insufficiency/diagnostic imaging , Female , Middle Aged , Ventricular Dysfunction, Right/physiopathology , Ventricular Dysfunction, Right/diagnostic imaging , Ventricular Dysfunction, Right/etiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/diagnosis , Aged , Retrospective Studies , Adult , Case-Control Studies , Risk Factors , Biomechanical Phenomena
19.
Cardiovasc Diabetol ; 23(1): 234, 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38965584

ABSTRACT

BACKGROUND: The abnormal low-density protein cholesterol (LDL-C) level in the development of atherosclerosis is often comorbid in individuals with type 2 diabetes mellitus(T2DM). This study aimed to investigate the aggravating effect of abnormal LDL-C levels on coronary artery plaques assessed by coronary computed tomography angiography (CCTA) in T2DM. MATERIALS AND METHODS: This study collected 3439 T2DM patients from September 2011 to February 2022. Comparative analysis of differences in coronary plaque characteristics was performed for the patients between the normal LDL-C level group and the abnormal LDL-C level group. Factors with P < 0.1 in the univariable linear regression analyses were included in the multivariable linear stepwise regression. RESULTS: A total of 2820 eligible T2DM patients were included and identified as the normal LDL-C level group (n = 973) and the abnormal LDL-C level group (n = 1847). Compared with the normal LDL-C level group, both on a per-patient basis and per-segment basis, patients with abnormal LDL-C level showed more calcified plaques, partially calcified plaques, low attenuation plaques, positive remodellings, and spotty calcifications. Multivessel obstructive disease (MVD), nonobstructive stenosis (NOS), obstructive stenosis (OS), plaque involvement degree (PID), segment stenosis score (SSS), and segment involvement scores (SIS) were likely higher in the abnormal LDL-C level group than that in the normal LDL-C level group (P < 0.001). In multivariable linear stepwise regression, the abnormal LDL-C level was validated as an independent positive correlation with high-risk coronary plaques and the degree and extent of stenosis caused by plaques (low attenuation plaque: ß = 0.116; positive remodelling: ß = 0.138; spotty calcification: ß = 0.091; NOS: ß = 0.427; OS: ß = 0.659: SIS: ß = 1.114; SSS: ß = 2.987; PID: ß = 2.716, all P value < 0.001). CONCLUSIONS: Abnormal LDL-C levels aggravate atherosclerotic cardiovascular disease (ASCVD) in patients with T2DM. Clinical attention deserves to be caught by the tailored identification of cardiovascular risk categories in T2DM individuals and the achievement of the corresponding LDL-C treatment goal.


Subject(s)
Biomarkers , Cholesterol, LDL , Computed Tomography Angiography , Coronary Angiography , Coronary Artery Disease , Diabetes Mellitus, Type 2 , Plaque, Atherosclerotic , Predictive Value of Tests , Vascular Calcification , Humans , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Male , Female , Middle Aged , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/blood , Coronary Artery Disease/epidemiology , Aged , Cholesterol, LDL/blood , Biomarkers/blood , Vascular Calcification/diagnostic imaging , Vascular Calcification/epidemiology , Vascular Calcification/blood , Risk Factors , Risk Assessment , Dyslipidemias/blood , Dyslipidemias/epidemiology , Dyslipidemias/diagnosis , Retrospective Studies , Coronary Vessels/diagnostic imaging , Severity of Illness Index , Prognosis , Cross-Sectional Studies
20.
Cardiovasc Diabetol ; 23(1): 317, 2024 Aug 27.
Article in English | MEDLINE | ID: mdl-39192259

ABSTRACT

BACKGROUND: Type 2 diabetes mellitus (T2DM) and metabolic-associated fatty liver disease (MAFLD) are both metabolic disorders that negatively impact the cardiovascular system. This study comprehensively analyzed the additive effect of MAFLD on left ventricular function and global strain in T2DM patients by cardiac magnetic resonance (CMR). METHODS: Data of 261 T2DM patients, including 109 with and 152 without MAFLD, as well as 73 matched normal controls from our medical center between June 2015 and March 2022 were retrospectively analyzed. CMR-derived parameters, including LV function and global strain parameters, were compared among different groups. Univariate and multivariate linear regression analyses were conducted to investigate the impact of various factors on LV function and global strain. RESULTS: Our investigation revealed a progressive deterioration in LV functional parameters across three groups: control subjects, T2DM patients without MAFLD, and T2DM patients with MAFLD. Statistically significant increases in left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), left ventricular mass index (LVMI) were observed, along with decreases in left ventricular ejection fraction (LVEF) and left ventricular global function index (LVGFI). Among these three groups, significant reductions were also noted in the absolute values of LV global radial, circumferential, and longitudinal peak strains (GRPS, GCPS, and GLPS), as well as in peak systolic (PSSR) and peak diastolic strain rates (PDSR). MAFLD was identified as an independent predictor of LVEF, LVMI, LVGFI, GRPS, GCPS, and GLPS in multivariate linear analysis. Besides, the incidence of late gadolinium enhancement was higher in MAFLD patients than in non-MAFLD patients (50/109 [45.9%] vs. 42/152 [27.6%], p = 0.003). Furthermore, escalating MAFLD severity was associated with a numerical deterioration in both LV function parameters and global strain values. CONCLUSIONS: This study thoroughly compared CMR parameters in T2DM patients with and without MAFLD, uncovering MAFLD's adverse impact on LV function and deformation in T2DM patients. These findings highlight the critical need for early detection and comprehensive management of cardiac function in T2DM patients with MAFLD.


Subject(s)
Diabetes Mellitus, Type 2 , Magnetic Resonance Imaging, Cine , Predictive Value of Tests , Ventricular Dysfunction, Left , Ventricular Function, Left , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/epidemiology , Male , Middle Aged , Female , Retrospective Studies , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/etiology , Aged , Risk Factors , Non-alcoholic Fatty Liver Disease/diagnostic imaging , Non-alcoholic Fatty Liver Disease/physiopathology , Non-alcoholic Fatty Liver Disease/complications , Stroke Volume , Adult , Diabetic Cardiomyopathies/physiopathology , Diabetic Cardiomyopathies/diagnostic imaging , Diabetic Cardiomyopathies/etiology , Biomechanical Phenomena
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