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1.
Immunity ; 54(7): 1611-1621.e5, 2021 07 13.
Article in English | MEDLINE | ID: mdl-34166623

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge during the global pandemic and may facilitate escape from current antibody therapies and vaccine protection. Here we showed that the South African variant B.1.351 was the most resistant to current monoclonal antibodies and convalescent plasma from coronavirus disease 2019 (COVID-19)-infected individuals, followed by the Brazilian variant P.1 and the United Kingdom variant B.1.1.7. This resistance hierarchy corresponded with Y144del and 242-244del mutations in the N-terminal domain and K417N/T, E484K, and N501Y mutations in the receptor-binding domain (RBD) of SARS-CoV-2. Crystal structure analysis of the B.1.351 triple mutant (417N-484K-501Y) RBD complexed with the monoclonal antibody P2C-1F11 revealed the molecular basis for antibody neutralization and escape. B.1.351 and P.1 also acquired the ability to use mouse and mink ACE2 receptors for entry. Our results demonstrate major antigenic shifts and potential broadening of the host range for B.1.351 and P.1 variants, which poses serious challenges to current antibody therapies and vaccine protection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/immunology , Immune Evasion , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/chemistry , Antigenic Variation/genetics , COVID-19/immunology , COVID-19/virology , Host Specificity , Humans , Immune Evasion/genetics , Mice , Mink , Mutation , Protein Binding , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
2.
Proc Natl Acad Sci U S A ; 121(35): e2321204121, 2024 Aug 27.
Article in English | MEDLINE | ID: mdl-39172782

ABSTRACT

Upon DNA damage, numerous proteins are targeted for ubiquitin-dependent proteasomal degradation, which is an integral part of the DNA repair program. Although details of the ubiquitination processes have been intensively studied, little is known about whether and how the 26S proteasome is regulated in the DNA damage response (DDR). Here, we show that human Rpn10/PSMD4, one of the three ubiquitin receptors of the 26S proteasome, is rapidly phosphorylated in response to different types of DNA damage. The phosphorylation occurs at Rpn10-Ser266 within a conserved SQ motif recognized by ATM/ATR/DNA-PK. Blockade of S266 phosphorylation attenuates homologous recombination-mediated DNA repair and sensitizes cells to genotoxic insults. In vitro and in cellulo experiments indicate that phosphorylation of S266, located in the flexible linker between the two ubiquitin-interacting motifs (UIMs) of Rpn10, alters the configuration of UIMs, and actually reduces ubiquitin chain (substrate) binding. As a result, essential DDR proteins such as BRCA1 are spared from premature degradation and allowed sufficient time to engage in DNA repair, a scenario supported by proximity labeling and quantitative proteomic studies. These findings reveal an inherent self-limiting mechanism of the proteasome that, by controlling substrate recognition through Rpn10 phosphorylation, fine-tunes protein degradation for optimal responses under stress.


Subject(s)
DNA Damage , DNA Repair , Proteasome Endopeptidase Complex , Proteasome Endopeptidase Complex/metabolism , Humans , Phosphorylation , Ubiquitin/metabolism , BRCA1 Protein/metabolism , Substrate Specificity , Ubiquitination , RNA-Binding Proteins
3.
Plant J ; 118(5): 1550-1568, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38412303

ABSTRACT

The increased soil salinity is becoming a major challenge to produce more crops and feed the growing population of the world. In this study, we demonstrated that overexpression of OsDIR55 gene enhances rice salt tolerance by altering the root diffusion barrier. OsDIR55 is broadly expressed in all examined tissues and organs with the maximum expression levels at lignified regions in rice roots. Salt stress upregulates the expression of OsDIR55 gene in an abscisic acid (ABA)-dependent manner. Loss-function and overexpression of OsDIR55 compromised and improved the development of CS and root diffusion barrier, manifested with the decreased and increased width of CS, respectively, and ultimately affected the permeability of the apoplastic diffusion barrier in roots. OsDIR55 deficiency resulted in Na+ accumulation, ionic imbalance, and growth arrest, whereas overexpression of OsDIR55 enhances salinity tolerance and provides an overall benefit to plant growth and yield potential. Collectively, we propose that OsDIR55 is crucial for ions balance control and salt stress tolerance through regulating lignification-mediated root barrier modifications in rice.


Subject(s)
Gene Expression Regulation, Plant , Oryza , Plant Proteins , Plant Roots , Salt Tolerance , Oryza/genetics , Oryza/physiology , Oryza/metabolism , Oryza/growth & development , Plant Roots/genetics , Plant Roots/physiology , Plant Roots/growth & development , Plant Roots/metabolism , Salt Tolerance/genetics , Plant Proteins/genetics , Plant Proteins/metabolism , Abscisic Acid/metabolism , Sodium/metabolism , Plants, Genetically Modified , Salt Stress/genetics
4.
Bioinformatics ; 40(5)2024 May 02.
Article in English | MEDLINE | ID: mdl-38613848

ABSTRACT

MOTIVATION: Identifying chromatin accessibility is one of the key steps in studying the regulation of eukaryotic genomes. The combination of exogenous methyltransferase and nanopore sequencing provides an strategy to identify open chromatin over long genomic ranges at the single-molecule scale. However, endogenous methylation, non-open-chromatin-specific exogenous methylation and base-calling errors limit the accuracy and hinders its application to complex genomes. RESULTS: We systematically evaluated the impact of these three influence factors, and developed a model-based computational method, methyltransferase accessible genome region finder (MAGNIFIER), to address the issues. By incorporating control data, MAGNIFIER attenuates the three influence factors with data-adaptive comparison strategy. We demonstrate that MAGNIFIER is not only sensitive to identify the open chromatin with much improved accuracy, but also able to detect the chromatin accessibility of repetitive regions that are missed by NGS-based methods. By incorporating long-read RNA-seq data, we revealed the association between the accessible Alu elements and non-classic gene isoforms. AVAILABILITY AND IMPLEMENTATION: Freely available on web at https://github.com/Goatofmountain/MAGNIFIER.


Subject(s)
Chromatin , Genome, Human , Nanopore Sequencing , Humans , Chromatin/metabolism , Chromatin/chemistry , Nanopore Sequencing/methods , Methyltransferases/metabolism , DNA Methylation
5.
Nature ; 565(7737): 49-55, 2019 01.
Article in English | MEDLINE | ID: mdl-30479383

ABSTRACT

The proteasome is an ATP-dependent, 2.5-megadalton molecular machine that is responsible for selective protein degradation in eukaryotic cells. Here we present cryo-electron microscopy structures of the substrate-engaged human proteasome in seven conformational states at 2.8-3.6 Å resolution, captured during breakdown of a polyubiquitylated protein. These structures illuminate a spatiotemporal continuum of dynamic substrate-proteasome interactions from ubiquitin recognition to substrate translocation, during which ATP hydrolysis sequentially navigates through all six ATPases. There are three principal modes of coordinated hydrolysis, featuring hydrolytic events in two oppositely positioned ATPases, in two adjacent ATPases and in one ATPase at a time. These hydrolytic modes regulate deubiquitylation, initiation of translocation and processive unfolding of substrates, respectively. Hydrolysis of ATP powers a hinge-like motion in each ATPase that regulates its substrate interaction. Synchronization of ATP binding, ADP release and ATP hydrolysis in three adjacent ATPases drives rigid-body rotations of substrate-bound ATPases that are propagated unidirectionally in the ATPase ring and unfold the substrate.


Subject(s)
Cryoelectron Microscopy , Proteasome Endopeptidase Complex/metabolism , Proteasome Endopeptidase Complex/ultrastructure , Adenosine Triphosphatases/metabolism , Adenosine Triphosphate/metabolism , Allosteric Regulation , Holoenzymes/chemistry , Holoenzymes/metabolism , Holoenzymes/ultrastructure , Humans , Hydrolysis , Models, Molecular , Proteasome Endopeptidase Complex/chemistry , Protein Conformation , Protein Structure, Quaternary , Protein Unfolding , Substrate Specificity , Ubiquitination
6.
Nature ; 574(7780): 722-725, 2019 10.
Article in English | MEDLINE | ID: mdl-31645759

ABSTRACT

The enzyme protochlorophyllide oxidoreductase (POR) catalyses a light-dependent step in chlorophyll biosynthesis that is essential to photosynthesis and, ultimately, all life on Earth1-3. POR, which is one of three known light-dependent enzymes4,5, catalyses reduction of the photosensitizer and substrate protochlorophyllide to form the pigment chlorophyllide. Despite its biological importance, the structural basis for POR photocatalysis has remained unknown. Here we report crystal structures of cyanobacterial PORs from Thermosynechococcus elongatus and Synechocystis sp. in their free forms, and in complex with the nicotinamide coenzyme. Our structural models and simulations of the ternary protochlorophyllide-NADPH-POR complex identify multiple interactions in the POR active site that are important for protochlorophyllide binding, photosensitization and photochemical conversion to chlorophyllide. We demonstrate the importance of active-site architecture and protochlorophyllide structure in driving POR photochemistry in experiments using POR variants and protochlorophyllide analogues. These studies reveal how the POR active site facilitates light-driven reduction of protochlorophyllide by localized hydride transfer from NADPH and long-range proton transfer along structurally defined proton-transfer pathways.


Subject(s)
Chlorophyll/biosynthesis , Oxidoreductases Acting on CH-CH Group Donors/chemistry , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Synechococcus/enzymology , Synechocystis/enzymology , Catalysis , Chlorophyll/chemistry , Molecular Structure , Photochemistry , Protochlorophyllide/metabolism , Structure-Activity Relationship , Substrate Specificity
7.
Nucleic Acids Res ; 51(21): 11634-11651, 2023 Nov 27.
Article in English | MEDLINE | ID: mdl-37870468

ABSTRACT

Bromodomain-containing protein 9 (BRD9) is a specific subunit of the non-canonical SWI/SNF (ncBAF) chromatin-remodeling complex, whose function in human embryonic stem cells (hESCs) remains unclear. Here, we demonstrate that impaired BRD9 function reduces the self-renewal capacity of hESCs and alters their differentiation potential. Specifically, BRD9 depletion inhibits meso-endoderm differentiation while promoting neural ectoderm differentiation. Notably, supplementation of NODAL, TGF-ß, Activin A or WNT3A rescues the differentiation defects caused by BRD9 loss. Mechanistically, BRD9 forms a complex with BRD4, SMAD2/3, ß-CATENIN and P300, which regulates the expression of pluripotency genes and the activity of TGF-ß/Nodal/Activin and Wnt signaling pathways. This is achieved by regulating the deposition of H3K27ac on associated genes, thus maintaining and directing hESC differentiation. BRD9-mediated regulation of the TGF-ß/Activin/Nodal pathway is also demonstrated in the development of pancreatic and breast cancer cells. In summary, our study highlights the crucial role of BRD9 in the regulation of hESC self-renewal and differentiation, as well as its participation in the progression of pancreatic and breast cancers.


Subject(s)
Human Embryonic Stem Cells , Neoplasms , Humans , Transforming Growth Factor beta/genetics , Human Embryonic Stem Cells/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Embryonic Stem Cells/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Cell Differentiation/genetics , Activins/metabolism , Wnt Signaling Pathway , Neoplasms/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism
8.
Nano Lett ; 24(25): 7572-7577, 2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38860969

ABSTRACT

Achieving high-temperature superlubricity is essential for modern extreme tribosystems. Solid lubrication is the sole viable alternative due to the degradation of liquid ones but currently suffers from notable wear, instability, and high friction coefficient. Here, we report robust superlubricity in MoS2/graphene van der Waals heterostructures at high temperatures up to ∼850 K, achieved through localized heating to enable reliable friction testing. The ultralow friction of the MoS2/graphene heterostructure is found to be notably further reduced at elevated temperature and dominantly contributed by the MoS2 edge. The observation can be well described by a multi-contact model, wherein the thermally activated rupture of edge-contacts facilitates the sliding. Our results should be applicable to other van der Waals heterostructures and shed light on their applications for superlubricity at elevated temperature.

9.
J Biol Chem ; 299(3): 102953, 2023 03.
Article in English | MEDLINE | ID: mdl-36731795

ABSTRACT

Acid-sensing ion channels (ASICs) play an important role in pain associated with tissue acidification. Peripheral inhibitory group II metabotropic glutamate receptors (mGluRs) have analgesic effects in a variety of pain conditions. Whether there is a link between ASICs and mGluRs in pain processes is still unclear. Herein, we show that the group II mGluR agonist LY354740 inhibited acid-evoked ASIC currents and action potentials in rat dorsal root ganglia neurons. LY354740 reduced the maximum current response to protons, but it did not change the sensitivity of ASICs to protons. LY354740 inhibited ASIC currents by activating group II mGluRs. We found that the inhibitory effect of LY354740 was blocked by intracellular application of the Gi/o protein inhibitor pertussis toxin and the cAMP analogue 8-Br-cAMP and mimicked by the protein kinase A (PKA) inhibitor H-89. LY354740 also inhibited ASIC3 currents in CHO cells coexpressing mGluR2 and ASIC3 but not in cells expressing ASIC3 alone. In addition, intraplantar injection of LY354740 dose-dependently alleviated acid-induced nociceptive behavior in rats through local group II mGluRs. Together, these results suggested that activation of peripheral group II mGluRs inhibited the functional activity of ASICs through a mechanism that depended on Gi/o proteins and the intracellular cAMP/PKA signaling pathway in rat dorsal root ganglia neurons. We propose that peripheral group II mGluRs are an important therapeutic target for ASIC-mediated pain.


Subject(s)
Acid Sensing Ion Channels , Ganglia, Spinal , Receptors, Metabotropic Glutamate , Sensory Receptor Cells , Animals , Cricetinae , Rats , Acid Sensing Ion Channels/metabolism , Cricetulus , Ganglia, Spinal/metabolism , Pain , Protons , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/metabolism , Sensory Receptor Cells/metabolism , Action Potentials , CHO Cells
10.
J Am Chem Soc ; 146(12): 8780-8786, 2024 03 27.
Article in English | MEDLINE | ID: mdl-38497732

ABSTRACT

The small RNAs on living cell membranes were recently found to be N-glycosylated and terminated with sialic acids, although the glycosylation sites and potential functions remain unclear. Herein, we designed a second-generation hierarchical coding strategy (HieCo 2) for in situ visualization of cell surface RNA-specific sialylation. After covalently binding DNA codes to sialic acids and then binding a DNA code to a target RNA via sequence specificity, cascade decoding processes were performed with subsequent signal amplification that enabled sensitive in situ visualization of low-abundance Y5 RNA-specific sialic acids on living cell membranes. The proposed strategy unveils the number of glycosylation sites on a single RNA and reveals the binding preference of glycosylated RNAs to different sialic acid binding-immunoglobulin lectin-type receptors, demonstrating a new route for exploration of the glycosylated RNA-related biological and pathological processes.


Subject(s)
RNA , Sialic Acids , Glycosylation , RNA/metabolism , Cell Membrane/metabolism , Sialic Acids/metabolism , DNA/metabolism , N-Acetylneuraminic Acid/metabolism
11.
Am J Physiol Gastrointest Liver Physiol ; 326(6): G697-G711, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38591127

ABSTRACT

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a widely expressed membrane glycoprotein that acts as an important modulator of lipid metabolism and inflammatory stress. N-glycosylation of SCAP has been suggested to modulate cancer development, but its role in nonalcoholic steatohepatitis (NASH) is poorly understood. In this study, the N-glycosylation of SCAP was analyzed by using sequential trypsin proteolysis and glycosidase treatment. The liver cell lines expressing wild-type and N-glycosylation sites mutated SCAP were constructed to investigate the N-glycosylation role of SCAP in regulating inflammation and lipid accumulation as well as the underlying mechanisms. The hepatic SCAP protein levels were significantly increased in C57BL/6J mice fed with Western diet and sugar water (WD + SW) and diabetic db/db mice, which exhibited typical liver steatosis and inflammation accompanied with hyperglycemia. In vitro, the enhanced N-glycosylation by high glucose increased the protein stability of SCAP and hence increased its total protein levels, whereas the ablation of N-glycosylation significantly decreased SCAP protein stability and alleviated lipid accumulation and inflammation in hepatic cell lines. Mechanistically, SCAP N-glycosylation increased not only the SREBP-1-mediated acetyl-CoA synthetase 2 (ACSS2) transcription but also the AMPK-mediated S659 phosphorylation of ACCS2 protein, causing the enhanced ACSS2 levels in nucleus and hence increasing the histone H3K27 acetylation (H3K27ac), which is a key epigenetic modification associated with NASH. Modulating ACSS2 expression or its location in the nuclear abolished the effects of SCAP N-glycosylation on H3K27ac and lipid accumulation and inflammation. In conclusion, SCAP N-glycosylation aggravates inflammation and lipid accumulation through enhancing ACSS2-mediated H3K27ac in hepatocytes.NEW & NOTEWORTHY N-glycosylation of SCAP exacerbates inflammation and lipid accumulation in hepatocytes through ACSS2-mediated H3K27ac. Our data suggest that SCAP N-glycosylation plays a key role in regulating histone H3K27 acetylation and targeting SCAP N-glycosylation may be a new strategy for treating nonalcoholic steatohepatitis (NASH).


Subject(s)
Histones , Intracellular Signaling Peptides and Proteins , Lipid Metabolism , Membrane Proteins , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease , Animals , Glycosylation , Histones/metabolism , Acetylation , Mice , Membrane Proteins/metabolism , Membrane Proteins/genetics , Lipid Metabolism/physiology , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Male , Humans , Liver/metabolism , Liver/pathology
12.
Pharmacogenomics J ; 24(2): 8, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38485921

ABSTRACT

BACKGROUND: Tibetan medicine Gaoyuan'an capsule (GYAC) is widely used to prevent pulmonary edema at high altitude, but the specific mechanism has not been explored. In this study, we analyzed the mechanism of GYAC in hypoxia tolerance, and provided a new idea for the prevention and treatment of altitude disease. METHODS: The effective components and corresponding targets of GYAC were screened out by the Chinese herbal medicine network database, and the key targets of hypoxia tolerance were retrieved by Genecards, OMIM and PubMed database. Cytoscape 3.7.2 was used to construct GYAC ingredient-target-hypoxia tolerance-related target network. GO function annotation and KEGG enrichment analysis were performed to predict the pathways in which target genes may be involved, and molecular docking was used to verify the binding ability of the compound to target genes. In vitro, the above results were further verified by molecular experiment. RESULTS: We found that GYAC can improve hypoxia tolerance by regulating various target genes, including IL6, IFNG, etc. The main regulatory pathways were HIF-1 signaling pathway. Molecular docking showed that the affinity between luteolin and target genes (IL6, IFNG) were better. In vitro, we observed that hypoxia can inhibit cell viability and promote apoptosis of H9C2 cell. And hypoxia can promote the expression of LDH. After the addition of luteolin, the decrease of cell viability, the increase of cell apoptosis, LDH release and the decrease of mitochondrial membrane potential were inhibited. Besides, inflammatory related factors (IL-6, IL-10, IL-2, IFNG and VEGFA) expression were also inhibited hypoxic cell models. CONCLUSIONS: The results of network pharmacology and molecular docking showed that luteolin, a monomeric component of GYAC, played a role in hypoxia tolerance through a variety of target genes, such as IL6, IFNG. What's more, we have discovered that luteolin can reduce the inflammatory response in cardiac myocytes, thereby alleviating mitochondrial damage, and ultimately enhancing the hypoxia tolerance of H9C2 cardiomyocytes.


Subject(s)
Drugs, Chinese Herbal , Interleukin-6 , Humans , Molecular Docking Simulation , Luteolin , Network Pharmacology , Hypoxia/drug therapy , Hypoxia/genetics , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use
13.
J Med Virol ; 96(2): e29445, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38299743

ABSTRACT

Membrane-associated RING-CH (MARCH) family proteins were recently reported to inhibit viral replication through multiple modes. Previous work showed that human MARCH8 blocked Ebola virus (EBOV) glycoprotein (GP) maturation. Our study here demonstrates that human MARCH1 and MARCH2 share a similar pattern to MARCH8 in restricting EBOV GP-pseudotyped viral infection. Human MARCH1 and MARCH2 retain EBOV GP at the trans-Golgi network, reduce its cell surface display, and impair EBOV GP-pseudotyped virions infectivity. Furthermore, we uncover that the host proprotein convertase furin could interact with human MARCH1/2 and EBOV GP intracellularly. Importantly, the furin P domain is verified to be recognized by MARCH1/2/8, which is critical for their blocking activities. Besides, bovine MARCH2 and murine MARCH1 also impair EBOV GP proteolytic processing. Altogether, our findings confirm that MARCH1/2 proteins of different mammalian origins showed a relatively conserved feature in blocking EBOV GP cleavage, which could provide clues for subsequent MARCHs antiviral studies and may facilitate the development of novel strategies to antagonize enveloped virus infection.


Subject(s)
Ebolavirus , Hemorrhagic Fever, Ebola , Animals , Cattle , Humans , Mice , Cell Line , Furin/metabolism , Glycoproteins , Mammals/metabolism , Membrane Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Viral Envelope/metabolism , Viral Envelope Proteins/genetics , Viral Envelope Proteins/metabolism
14.
Metabolomics ; 20(3): 57, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38773045

ABSTRACT

BACKGROUND: Despite the clear clinical diagnostic criteria for necrozoospermia in andrology, the fundamental mechanisms underlying it remain elusive. This study aims to profile the lipid composition in seminal plasma systematically and to ascertain the potential of lipid biomarkers in the accurate diagnosis of necrozoospermia. It also evaluates the efficacy of a lipidomics-based random forest algorithm model in identifying necrozoospermia. METHODS: Seminal plasma samples were collected from patients diagnosed with necrozoospermia (n = 28) and normozoospermia (n = 28). Liquid chromatography-mass spectrometry (LC-MS) was used to perform lipidomic analysis and identify the underlying biomarkers. A lipid functional enrichment analysis was conducted using the LION lipid ontology database. The top 100 differentially significant lipids were subjected to lipid biomarker examination through random forest machine learning model. RESULTS: Lipidomic analysis identified 46 lipid classes comprising 1267 lipid metabolites in seminal plasma. The top five enriched lipid functions as follows: fatty acid (FA) with ≤ 18 carbons, FA with 16-18 carbons, monounsaturated FA, FA with 18 carbons, and FA with 16 carbons. The top 100 differentially significant lipids were subjected to machine learning analysis and identified 20 feature lipids. The random forest model identified lipids with an area under the curve > 0.8, including LPE(20:4) and TG(4:0_14:1_16:0). CONCLUSIONS: LPE(20:4) and TG(4:0_14:1_16:0), were identified as differential lipids for necrozoospermia. Seminal plasma lipidomic analysis could provide valuable biochemical information for the diagnosis of necrozoospermia, and its combination with conventional sperm analysis may improve the accuracy and reliability of the diagnosis.


Subject(s)
Algorithms , Lipidomics , Semen , Adult , Humans , Male , Biomarkers/blood , Infertility, Male/diagnosis , Infertility, Male/metabolism , Lipidomics/methods , Lipids/analysis , Lipids/blood , Machine Learning , Random Forest , Semen/metabolism , Semen/chemistry , Liquid Chromatography-Mass Spectrometry
15.
Cancer Invest ; 42(6): 527-537, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38965994

ABSTRACT

Despite the emergence of various treatment strategies for rectal cancer based on neoadjuvant chemoradiotherapy, there is currently a lack of reliable biomarkers to determine which patients will respond well to neoadjuvant chemoradiotherapy. Through collecting hematological and biochemical parameters data of patients prior to receiving neoadjuvant chemoradiotherapy, we evaluated the predictive value of systemic inflammatory indices for pathological response and prognosis in rectal cancer patients. We found that baseline GRIm-Score was an independent predictor for MPR in rectal cancer patients. However, no association was observed between several commonly systemic inflammation indices and long-term outcome.


Subject(s)
Neoadjuvant Therapy , Rectal Neoplasms , Humans , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Rectal Neoplasms/immunology , Male , Female , Middle Aged , Neoadjuvant Therapy/methods , Aged , Chemoembolization, Therapeutic/methods , Prognosis , Treatment Outcome , Adult , Chemoradiotherapy/methods
16.
Psychol Med ; 54(3): 582-591, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37553976

ABSTRACT

BACKGROUND: The age-related heterogeneity in major depressive disorder (MDD) has received significant attention. However, the neural mechanisms underlying such heterogeneity still need further investigation. This study aimed to explore the common and distinct functional brain abnormalities across different age groups of MDD patients from a large-sample, multicenter analysis. METHODS: The analyzed sample consisted of a total of 1238 individuals including 617 MDD patients (108 adolescents, 12-17 years old; 411 early-middle adults, 18-54 years old; and 98 late adults, > = 55 years old) and 621 demographically matched healthy controls (60 adolescents, 449 early-middle adults, and 112 late adults). MDD-related abnormalities in brain functional connectivity (FC) patterns were investigated in each age group separately and using the whole pooled sample, respectively. RESULTS: We found shared FC reductions among the sensorimotor, visual, and auditory networks across all three age groups of MDD patients. Furthermore, adolescent patients uniquely exhibited increased sensorimotor-subcortical FC; early-middle adult patients uniquely exhibited decreased visual-subcortical FC; and late adult patients uniquely exhibited wide FC reductions within the subcortical, default-mode, cingulo-opercular, and attention networks. Analysis of covariance models using the whole pooled sample further revealed: (1) significant main effects of age group on FCs within most brain networks, suggesting that they are decreased with aging; and (2) a significant age group × MDD diagnosis interaction on FC within the default-mode network, which may be reflective of an accelerated aging-related decline in default-mode FCs. CONCLUSIONS: To summarize, these findings may deepen our understanding of the age-related biological and clinical heterogeneity in MDD.


Subject(s)
Depressive Disorder, Major , Adult , Humans , Adolescent , Child , Young Adult , Middle Aged , Magnetic Resonance Imaging , Brain/diagnostic imaging , Brain Mapping , Insular Cortex
17.
Transgenic Res ; 33(4): 195-210, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39105946

ABSTRACT

Ethylene response factors have been shown to be involved in the effects of plant developmental processes and to regulate stress tolerance. The aim of this study was to recognize the regulatory mechanisms of ethylene response factors on tobacco plant height. In this study, a gene-edited mutant (ERF10-KO) and wild type (WT) were utilized as experimental materials. Transcriptome and metabolome analyses were used to investigate the regulatory mechanism of NtERF10 gene editing on plant height in tobacco. Here, through the analysis of differentially expressed genes (DEGs), 2051 genes were upregulated and 1965 genes were downregulated. We characterized the different ERF10-KO and WT plant heights and identified key genes for photosynthesis, the plant hormone signal transduction pathway and the terpene biosynthesis pathway. NtERF10 was found to affect the growth and development of tobacco by regulating the expression levels of the PSAA, PSBA, GLY17 and GGP3 genes. Amino acid metabolism was analyzed by combining analyses of differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs). In addition, we found that members of the bHLH, NAC, MYB, and WRKY transcription factor families have vital roles in regulating plant height. This study not only provides important insights into the positive regulation of the ethylene response factor NtERF10 on plant height during plant growth and development but also provides new research ideas for tobacco molecular breeding.


Subject(s)
Gene Expression Regulation, Plant , Nicotiana , Plant Proteins , Transcription Factors , Nicotiana/genetics , Nicotiana/growth & development , Nicotiana/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Plant Growth Regulators/metabolism , Plant Growth Regulators/genetics , Ethylenes/metabolism , Plants, Genetically Modified/growth & development , Plants, Genetically Modified/genetics , Plants, Genetically Modified/metabolism , Transcriptome
18.
Neurochem Res ; 49(5): 1254-1267, 2024 May.
Article in English | MEDLINE | ID: mdl-38381246

ABSTRACT

Fibrotic scars play important roles in tissue reconstruction and functional recovery in the late stage of nervous system injury. However, the mechanisms underlying fibrotic scar formation and regulation remain unclear. Casein kinase II (CK2) is a protein kinase that regulates a variety of cellular functions through the phosphorylation of proteins, including bromodomain-containing protein 4 (BRD4). CK2 and BRD4 participate in fibrosis formation in a variety of tissues. However, whether CK2 affects fibrotic scar formation remains unclear, as do the mechanisms of signal regulation after cerebral ischemic injury. In this study, we assessed whether CK2 could modulate fibrotic scar formation after cerebral ischemic injury through BRD4. Primary meningeal fibroblasts were isolated from neonatal rats and treated with transforming growth factor-ß1 (TGF-ß1), SB431542 (a TGF-ß1 receptor kinase inhibitor) or TBB (a highly potent CK2 inhibitor). Adult SD rats were intraperitoneally injected with TBB to inhibit CK2 after MCAO/R. We found that CK2 expression was increased in vitro in the TGF-ß1-induced fibrosis model and in vivo in the MCAO/R injury model. The TGF-ß1 receptor kinase inhibitor SB431542 decreased CK2 expression in fibroblasts. The CK2 inhibitor TBB reduced the increases in proliferation, migration and activation of fibroblasts caused by TGF-ß1 in vitro, and it inhibited fibrotic scar formation, ameliorated histopathological damage, protected Nissl bodies, decreased infarct volume and alleviated neurological deficits after MCAO/R injury in vivo. Furthermore, CK2 inhibition decreased BRD4 phosphorylation both in vitro and in vivo. The findings of the present study suggested that CK2 may control BRD4 phosphorylation to regulate fibrotic scar formation, to affecting outcomes after ischemic stroke.


Subject(s)
Benzamides , Bromodomain Containing Proteins , Casein Kinase II , Cicatrix , Dioxoles , Ischemic Stroke , Animals , Rats , Casein Kinase II/antagonists & inhibitors , Casein Kinase II/metabolism , Cicatrix/metabolism , Cicatrix/pathology , Fibroblasts/metabolism , Fibrosis , Ischemic Stroke/complications , Ischemic Stroke/drug therapy , Ischemic Stroke/metabolism , Nuclear Proteins , Phosphorylation , Rats, Sprague-Dawley , Transcription Factors/metabolism , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta1/pharmacology , Bromodomain Containing Proteins/drug effects , Bromodomain Containing Proteins/metabolism
19.
J Surg Res ; 296: 18-28, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38215673

ABSTRACT

INTRODUCTION: Ventricular septal defect (VSD) is the most common congenital heart malformation in children. This study aimed to investigate potential pathogenic genes associated with Tibetan familial VSD. METHODS: Whole genomic DNA was extracted from eight Tibetan children with VSD and their healthy parents (a total of 16 individuals). Whole-exome sequencing was performed using the Illumina HiSeq platform. After filtration, detection, and annotation, single nucleotide variations and insertion-deletion markers were examined. Comparative evaluations using the Sorting Intolerant from Tolerant, PolyPhen V2, Mutation Taster, and Combined Annotation Dependent Depletion databases were conducted to predict harmful mutant genes associated with the etiology of Tibetan familial VSD. RESULTS: A total of six missense mutations in genetic disease-causing genes associated with the development of Tibetan familial VSD were identified: activin A receptor type II-like 1 (c.652 C > T: p.R218 W), ATPase cation transporting 13A2 (c.1363 C > T: p.R455 W), endoplasmic reticulum aminopeptidase 1 (c.481 G > A: p.G161 R), MRI1 (c.629 G > A: p.R210Q), tumor necrosis factor receptor-associated protein 1 (c.224 G > A: p.R75H), and FBN2 (c.2260 G > A: p.G754S). The Human Gene Mutation Database confirmed activin A receptor type II-like 1, MRI1, and tumor necrosis factor receptor-associated protein 1 as pathogenic mutations, while FBN2 was classified as a probable pathogenic mutation. CONCLUSIONS: This novel study directly screens genetic variations associated with Tibetan familial VSD using whole-exome sequencing, providing new insights into the pathogenesis of VSD.


Subject(s)
Heart Defects, Congenital , Heart Septal Defects, Ventricular , Child , Humans , Exome Sequencing , Tibet , Heart Septal Defects, Ventricular/genetics , Heart Septal Defects, Ventricular/metabolism , Receptors, Tumor Necrosis Factor/genetics
20.
Nanotechnology ; 35(12)2024 Jan 04.
Article in English | MEDLINE | ID: mdl-38100843

ABSTRACT

Mucosal delivery systems have gained much attention as effective way for antigen delivery that induces both systemic and mucosal immunity. However, mucosal vaccination faces the challenges of mucus barrier and effective antigen uptake and presentation. In particular, split, subunit and recombinant protein vaccines that do not have an intact pathogen structure lack the efficiency to stimulate mucosal immunity. In this study, poly (lactic acid-co-glycolic acid-polyethylene glycol) (PLGA-PEG) block copolymers were modified by mannose to form a PLGA-PEG-Man conjugate (mannose modified PLGA-PEG), which were characterized. The novel nanoparticles (NPs) prepared with this material had a particle size of about 150 nm and a zeta potential of -15 mV, and possessed ideal mucus permeability, immune cell targeting, stability and low toxicity. Finally, PLGA-PEG-Man nanoparticles (PLGA-PEG-Man NPs) were successfully applied for intranasal delivery of split influenza vaccine in rat for the first time, which triggered strong systemic and mucosal immune responses. These studies suggest that PLGA-PEG-Man NPs could function as competitive potential nano-adjuvants to address the challenge of inefficient mucosal delivery of non-allopathogenic antigens.


Subject(s)
Influenza Vaccines , Nanoparticles , Humans , Rats , Animals , Polylactic Acid-Polyglycolic Acid Copolymer , Polyglycolic Acid/chemistry , Lactic Acid/chemistry , Mannose , Adjuvants, Immunologic/pharmacology , Antigens , Nanoparticles/chemistry
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