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1.
Article in English | MEDLINE | ID: mdl-38981976

ABSTRACT

Platelet hyperreactivity is one of the crucial causes of coagulative disorders in patients with COVID-19. Few studies have indicated that integrin αIIbß3 may be a potential target for spike protein binding to platelets. This study aims to investigate whether spike protein interacts with platelet integrin αIIbß3 and upregulates outside-in signaling to potentiate platelet aggregation. In this study, we found that spike protein significantly potentiated platelet aggregation induced by different agonists and platelet spreading in vitro. Mechanism studies revealed that spike protein upregulated the outside-in signaling, such as increased thrombin-induced phosphorylation of ß3, c-Src. Moreover, using tirofiban to inhibit spike protein binding to αIIbß3 or using PP2 to block outside-in signaling, we found that the potentiating effect of spike protein on platelet aggregation was abolished. These results demonstrate that SARS-CoV-2 spike protein directly enhances platelet aggregation via integrin αIIbß3 outside-in signaling, and suggest a potential target for platelet hyperreactivity in patients with COVID-19. HIGHLIGHTS: • Spike protein potentiates platelet aggregation and upregulates αIIbß3 outside-in signaling. • Spike protein interacts with integrin αIIbß3 to potentiate platelet aggregation. • Blocking outside-in signaling abolishes the effect of spike protein on platelets.

2.
Cell Biochem Funct ; 42(4): e4039, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38751189

ABSTRACT

Platelet hyperreactivity contributes to the pathogenesis of COVID-19, which is associated with a hypercoagulability state and thrombosis disorder. It has been demonstrated that Vitamin D deficiency is associated with the severity of COVID-19 infection. Vitamin D supplement is widely used as a dietary supplement due to its safety and health benefits. In this study, we investigated the direct effects and underlying mechanisms of 1,25(OH)2D3 on platelet hyperreactivity induced by SRAS-CoV-2 spike protein via Western blot and platelet functional studies in vitro. Firstly, we found that 1,25(OH)2D3 attenuated platelet aggregation and Src-mediated signaling. We further observed that 1,25(OH)2D3 attenuated spike protein-potentiated platelet aggregation in vitro. Mechanistically, 1,25(OH)2D3 attenuated spike protein upregulated-integrin αIIbß3 outside-in signaling such as platelet spreading and the phosphorylation of ß3, c-Src and Syk. Moreover, using PP2, the Src family kinase inhibitor to abolish spike protein-stimulated platelet aggregation and integrin αIIbß3 outside-in signaling, the combination of PP2 and 1,25(OH)2D3 did not show additive inhibitory effects on spike protein-potentiated platelet aggregation and the phosphorylation of ß3, c-Src and Syk. Thus, our data suggest that 1,25(OH)2D3 attenuates platelet aggregation potentiated by spike protein via downregulating integrin αIIbß3 outside-in signaling.


Subject(s)
Platelet Aggregation , Platelet Glycoprotein GPIIb-IIIa Complex , Signal Transduction , Spike Glycoprotein, Coronavirus , Platelet Aggregation/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Humans , Signal Transduction/drug effects , SARS-CoV-2/drug effects , COVID-19/metabolism , Blood Platelets/metabolism , Blood Platelets/drug effects , Calcitriol/pharmacology , src-Family Kinases/metabolism , src-Family Kinases/antagonists & inhibitors , Syk Kinase/metabolism , Syk Kinase/antagonists & inhibitors , Phosphorylation/drug effects , COVID-19 Drug Treatment
3.
BMC Neurol ; 24(1): 153, 2024 May 04.
Article in English | MEDLINE | ID: mdl-38704548

ABSTRACT

OBJECTIVE: Sex differences in outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH) remain controversial. Therefore, the aim of this study was to investigate the sex differences in the prognosis of patients with aSAH. METHODS: This study retrospectively analyzed the clinical data of aSAH patients admitted to the Department of Neurosurgery of General Hospital of Northern Theater Command, from April 2020 to January 2022. The modified Rankin Scale (mRS) was used to evaluate outcomes at 3-month post-discharge. Baseline characteristics, in-hospital complications and outcomes were compared after 1:1 propensity score matching (PSM). RESULTS: A total of 665 patients were included and the majority (63.8%) were female. Female patients were significantly older than male patients (59.3 ± 10.9 years vs. 55.1 ± 10.9 years, P < 0.001). After PSM, 141 male and 141 female patients were compared. Comparing postoperative complications and mRS scores, the incidence of delayed cerebral ischemia (DCI) and hydrocephalus and mRS ≥ 2 at 3-month were significantly higher in female patients than in male patients. After adjustment, the analysis of risk factors for unfavorable prognosis at 3-month showed that age, sex, smoking, high Hunt Hess grade, high mFisher score, DCI, and hydrocephalus were independent risk factors. CONCLUSION: Female patients with aSAH have a worse prognosis than male patients, and this difference may be because females are more vulnerable to DCI and hydrocephalus.


Subject(s)
Propensity Score , Subarachnoid Hemorrhage , Humans , Subarachnoid Hemorrhage/epidemiology , Subarachnoid Hemorrhage/diagnosis , Subarachnoid Hemorrhage/surgery , Male , Female , Middle Aged , Aged , Retrospective Studies , Adult , Sex Characteristics , Sex Factors , Prognosis , Treatment Outcome , Postoperative Complications/epidemiology , Risk Factors
4.
Clin Genet ; 2024 May 15.
Article in English | MEDLINE | ID: mdl-38747114

ABSTRACT

Type IV collagen is an integral component of basement membranes. Mutations in COL4A1, one of the key genes encoding Type IV collagen, can result in a variety of diseases. It is clear that a significant proportion of mutations that affect splicing can cause disease directly or contribute to the susceptibility or severity of disease. Here, we analyzed exonic mutations and intronic mutations described in the COL4A1 gene using bioinformatics programs and identified candidate mutations that may alter the normal splicing pattern through a minigene system. We identified seven variants that induce splicing alterations by disrupting normal splice sites, creating new ones, or altering splice regulatory elements. These mutations are predicted to impact protein function. Our results help in the correct molecular characterization of variants in COL4A1 and may help develop more personalized treatment options.

5.
Immun Inflamm Dis ; 11(10): e1041, 2023 10.
Article in English | MEDLINE | ID: mdl-37904711

ABSTRACT

OBJECTIVE: To investigate the clinical efficacy of plasma exchange (PE) with or without prednisone and hydroxychloroquine (HCQ) for the treatment of systemic lupus erythematosus (SLE) during pregnancy. METHODS: The clinical characteristics of 14 pregnant women with SLE admitted to our hospital were retrospectively analyzed, including 7 only treated with prednisone and HCQ (non-PE group) as well as 7 combined PE (PE group). The delivery situations of 14 patients were recorded. Data like erythrocyte sedimentation rate (ESR), urine protein, platelet count, and SLEDAI scores were compared between two groups before treatment and 3, 6, and 12 months after delivery. RESULTS: Three patients in the non-PE group ended in miscarriage while all patients in the PE group were delivered successfully. Eleven successfully delivered fetuses in the two groups were healthy, and the Apgar scores were over 8. The ESR of the PE group was significantly lower than that of the non-PE group at 6 and 12 months after delivery, while there was no statistical difference in ESR between the two groups before treatment and 3 months after delivery. The ESR and urine protein were significantly higher in the non-PE group at months 3, 6, and 12 postpartum. There was a significant decrease in disease activity postpartum in the PE group compared to predelivery disease activity. The change in platelet counts between the two groups significantly increased over time in the PE group, while SLEDAI scores decreased. CONCLUSIONS: The combination of PE and oral prednisone and HCQ is possibly a more effective treatment than oral prednisone and HCQ alone for patients with active SLE during pregnancy. This treatment option reduces pregnancy loss and promotes the patients' postpartum condition to a certain extent.


Subject(s)
Antirheumatic Agents , Lupus Erythematosus, Systemic , Humans , Female , Pregnancy , Prednisone/therapeutic use , Antirheumatic Agents/adverse effects , Retrospective Studies , Plasma Exchange , Lupus Erythematosus, Systemic/therapy , Hydroxychloroquine , Treatment Outcome
6.
Front Cell Infect Microbiol ; 13: 1130333, 2023.
Article in English | MEDLINE | ID: mdl-36936768

ABSTRACT

Introduction: Tigecycline and carbapenems are considered the last line of defense against microbial infections. The co-occurrence of resistance genes conferring resistance to both tigecycline and carbapenems in Pseudomononas asiatica was not investigated. Methods: P. asiatica A28 was isolated from hospital sewage. Antibiotic susceptibility testing showed resistance to carbapenem and tigecycline. WGS was performed to analyze the antimicrobial resistance genes and genetic characteristics. Plasmid transfer by conjugation was investigated. Plasmid fitness costs were evaluated in Pseudomonas aeruginosa transconjugants including a Galleria mellonella infection model. Results: Meropenem and tigecycline resistant P. asiatica A28 carries a 199, 972 bp long plasmid PLA28.4 which harbors seven resistance genes. Sequence analysis showed that the 7113 bp transposon Tn7389 is made up of a class I integron without a 5'CS terminal and a complete tni module flanked by a pair of 25bp insertion repeats. Additionally, the Tn7493 transposon, 20.24 kp long, with a complete 38-bp Tn1403 IR and an incomplete 30-bp Tn1403 IR, is made up of partial skeleton of Tn1403, a class I integron harboring bla OXA-10, and a Tn5563a transposon. Moreover, one tnfxB3-tmexC3.2-tmexD3b-toprJ1b cluster was found in the plasmid and another one in the the chromosome. Furthermore, plasmid PLA28.4 could be conjugated to P. aeruginosa PAO1, with high fitness cost. Discussion: A multidrug-resistant plasmid carrying tmexCD3-toprJ1b and two novel transposons carrying bla VIM-2 and bla OXA-10 -resistant genes was found in hospital sewage, increasing the risk of transmission of antibiotic-resistant genes. These finding highlight the necessary of controlling the development and spread of medication resistance requires continuous monitoring and management of resistant microorganisms in hospital sewage.


Subject(s)
Pseudomonas Infections , Sewage , Humans , Tigecycline , beta-Lactamases/genetics , Plasmids/genetics , Anti-Bacterial Agents/pharmacology , Carbapenems , Microbial Sensitivity Tests
7.
Appl Opt ; 62(1): 27-33, 2023 Jan 01.
Article in English | MEDLINE | ID: mdl-36606845

ABSTRACT

A resistive switch effect-based optical memristive switch with an ultra-high extinction ratio and ultra-compact size working at 1550 nm is proposed. The device is composed of a metal-insulator-metal waveguide and a square resonator with active electrodes. The formation and rupture of conductive filaments in the resonant cavity can alter the resonant wavelength, which triggers the state of the optical switch ON or OFF. The numerical results demonstrate that the structure has an ultra-compact size (less than 1 µm) and ultra-high extinction ratio (37 dB). The proposed device is expected to address the problems of high-power consumption and large-scale optical switches and can be adopted in optical switches, optical modulation, optical storage and computing, and large-scale photonic integrated devices.

8.
Int J Mol Sci ; 23(20)2022 Oct 15.
Article in English | MEDLINE | ID: mdl-36293203

ABSTRACT

Platelet hyperreactivity and oxidative stress are the important causes of thrombotic disorders in patients with COVID-19. Oxidative stress, induced by the excessive generation of reactive oxygen species (ROS), could increase platelet function and the risk of thrombus formation. Coenzyme Q10 (CoQ10), exhibits strong antioxidative activity and anti-platelet effect. However, the effects and mechanisms of CoQ10 on attenuating platelet aggregation induced by spike protein have never been studied. This study aims to investigate whether the SARS-CoV-2 spike protein potentiates human platelet function via ROS signaling and the protective effect of CoQ10 in vitro. Using a series of platelet function assays, we found that spike protein potentiated platelet aggregation and oxidative stress, such as ROS level, mitochondrial membrane potential depolarization, and lipid damage level (MDA and 8-iso-PGF2α) in vitro. Furthermore, CoQ10 attenuated platelet aggregation induced by spike protein. As an anti-platelet mechanism, we showed that CoQ10 significantly decreased the excess production of ROS induced by spike protein. Our findings show that the protective effect of CoQ10 on spike protein-potentiated platelet aggregation is probably associated with its strong antioxidative ability.


Subject(s)
COVID-19 Drug Treatment , Spike Glycoprotein, Coronavirus , Humans , Spike Glycoprotein, Coronavirus/metabolism , Reactive Oxygen Species/metabolism , Platelet Aggregation , SARS-CoV-2 , Ubiquinone/pharmacology , Ubiquinone/metabolism , Oxidative Stress , Antioxidants/pharmacology , Antioxidants/metabolism , Lipids/pharmacology
9.
Chemosphere ; 299: 134375, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35314181

ABSTRACT

As some of the most promising alternatives to traditional non-degradable materials, photodegradable materials have advantages of environmental benignity and rapid degradation under simple conditions. In this work, nontoxic TiO2 and cost-effective g-C3N4 have been compounded in a weight of 9:1 to form a photocatalytic additive with high activity. A 25 wt% loading of this photocatalytic additive has been incorporated into the polyacrylonitrile (PAN) by centrifugal electrospinning to prepare an abiotic degradable PAN material. Our results showed that the PAN chain could be almost fully degraded within 90 h in an aqueous medium under simulated sunlight in the absence of microorganisms. Product analysis implied that degradation of the PAN chain mainly involved the breaking of -CN and C-C bonds by radicals, followed by oxidation of terminal groups to carboxyl and gradual mineralization to CO2 and H2O. This design strategy may provide new insight for the production and degradation mechanism of photodegradable polymer.


Subject(s)
Lighting , Sunlight , Acrylic Resins , Catalysis , Titanium
10.
Sci Rep ; 11(1): 12178, 2021 06 09.
Article in English | MEDLINE | ID: mdl-34108502

ABSTRACT

Purine rich element binding protein A (Purα), encoded by the Purα gene, is an important transcriptional regulator that binds to DNA and RNA and is involved in processes such as DNA replication and RNA translation. Purα also plays an important role in the nervous system. To identify the function of Pura, we performed RNA sequence (RNA-seq) analysis of Purɑ-KO mouse hippocampal neuron cell line (HT22) to analyze the effect of Purα deletion on neuronal expression profiles. And combined with ChIP-seq analysis to explore the mechanism of Purα on gene regulation. In the end, totaly 656 differentially expressed genes between HT22 and Purα-KO HT22 cells have been found, which include 7 Alzheimer's disease (AD)-related genes and 5 Aß clearance related genes. 47 genes were regulated by Purα directly, the evidence based on CHIP-seq, which include Insr, Mapt, Vldlr, Jag1, etc. Our study provides the important informations of Purα in neuro-development. The possible regulative effects of Purα on AD-related genes consist inthe direct and indirect pathways of Purα in the pathogenesis of AD.


Subject(s)
Alzheimer Disease/pathology , Chromatin Immunoprecipitation Sequencing/methods , DNA-Binding Proteins/metabolism , Hippocampus/pathology , Nerve Tissue Proteins/metabolism , Neurons/pathology , RNA-Seq/methods , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Animals , DNA-Binding Proteins/genetics , Hippocampus/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Tissue Proteins/genetics , Neurons/metabolism
11.
BMC Immunol ; 20(1): 32, 2019 09 04.
Article in English | MEDLINE | ID: mdl-31484501

ABSTRACT

BACKGROUND: The development of Systemic lupus erythematosus (SLE) has been associated with the balance of Th17 and Treg cells. IL-2 and rapamycin can influence the populations of both Th17 and Treg cells. However, it is unclear whether low dose of IL-2 and rapamycin can relieve the symptoms of SLE patients and what is the mechanisms. In this study, we aim to analyze the effect of low dose of IL-2 plus rapamycin on the number of Tregs, Th17 cells and the ratio of Th17/Treg cells, as well as to evaluate its therapeutic efficacy in refractory SLE patients. RESULT: Fifty refractory SLE patients and 70 healthy controls were enrolled and followed up for 24 weeks. We found that compared with HC, the refractory SLE patients had a lower number of Tregs, a similar number of Th17 cells, but an increased ratio of Th17/Treg. After the treatment, the number of Tregs of the patients at 12th and 24th week was significantly increased. While the number of Th17 cells was unchanged, the ratio of Th17/Treg was significantly decreased at both 6 weeks and 24 weeks. After 6, 12 and 24 weeks of treatment, the SLEDAI score was significantly reduced. The prednison dosage at 6th,12th and 24th week post treatment was significantly decreased. CONCLUSION: Our results support that the reduction of Tregs and the imbalance of Th17/Treg cells were correlated with the occurrence and development of refractory SLE. Low dose of IL-2 combined with rapamycin was able to restore the number of Tregs and the balance of Th17/Treg cells. As a result, this approach was able to induce immune tolerance and promote disease remission, allowing for the reduction in prednisone dosage. TRIAL REGISTRATION: ChiCTR-IPR-16009451 Registration date: 2016/10/16.


Subject(s)
Interleukin-2/pharmacology , Lupus Erythematosus, Systemic/immunology , Sirolimus/pharmacology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Th17 Cells/drug effects , Th17 Cells/immunology , Adult , Biomarkers , Drug Synergism , Drug Therapy, Combination , Female , Humans , Interleukin-2/administration & dosage , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/metabolism , Lymphocyte Count , Male , Middle Aged , Severity of Illness Index , Sirolimus/administration & dosage , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/metabolism , Treatment Outcome
12.
Neuroscience ; 398: 1-11, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30529264

ABSTRACT

Dravet syndrome (DS) is a disease that is primarily caused by the inactivation of the SCN1A-encoded voltage-gated sodium channel alpha subunit (Nav1.1). In this study, we constructed an SCN1A gene knockout model using CRISPR/Cas9 genome editing technology to deprive the Nav1.1 function in vitro. With mRNA-seq analysis we found abundant gene changes after SCN1A knockout, which associated with various signaling pathways, such as cancer pathways, the PI3K-AKT signaling pathway, the MAPK signaling pathway, and pathways involved in HTLV-I infection. We also noticed changes in the spliceosome, decreased glycolytic capacity, disturbances in calcium signaling pathways, and changes in the potassium, sodium, chloride, and calcium plasma channels after SCN1A knockout. In this study, we have been the first time to discover these changes and summarize them here and hope it would provide some clue for the study of Nav1.1 in the nervous system.


Subject(s)
CRISPR-Cas Systems , Gene Editing , Gene Knockout Techniques , NAV1.1 Voltage-Gated Sodium Channel/deficiency , Animals , Cell Line , Epilepsies, Myoclonic/genetics , Epilepsies, Myoclonic/metabolism , Gene Expression , Gene Knockout Techniques/methods , Mice , NAV1.1 Voltage-Gated Sodium Channel/genetics , RNA, Messenger/metabolism , Sequence Analysis, RNA , Signal Transduction
13.
Nephrology (Carlton) ; 21(10): 828-34, 2016 Oct.
Article in English | MEDLINE | ID: mdl-26609639

ABSTRACT

AIM: Renal ischaemia/reperfusion injury (IRI) is a complication of major surgeries. Regulatory T cells (Tregs) can suppress immunologic damage in the renal IR. Previous studies indicated that delayed ischaemic preconditioning (IPC) partially attenuates IR by inducing Treg expansion. Galectin-9 also attenuates inflammation-related organ injury by expanding Tregs, but it was not used in renal IR yet. Our aim was to test whether IPC combined with galectin-9 has an increased renoprotective effect. METHODS: Mice were divided into five treatment groups (n = 6 per group): (i) IR group: renal ischaemia/reperfusion group; (ii) IPC-IR group: IPC followed by renal IR; (iii) IPC-Gal9-IR group: Gal-9 injections during the time between IPC and IR; (iv) IPC-Gal9-PC61-IR group: anti-CD25 antibody administration apart from IPC, Gal-9 and IR; (v) sham-sham group. We assessed the renal function, histopathological scores, and percentages of Tregs and interferon-γ (IFN-γ) cells in peripheral bood, spleen, and kidney and compared these values among the different groups. RESULTS: Serum creatinine measured was significantly lower after IPC and even lower in combination with Gal-9 injection. The histopathological scores for tubulo-interstitial injury were decreased following IPC and markedly lower after the addition of Gal-9. The number of kidney infiltrating neutrophils and IFN-γ secreting CD4+ T cells was diminished in the IPC/Gal9 combination group, while the percentage of Treg cells in the peripheral blood, spleen, and kidney of animals from the IPC-Gal9-IR group was also markedly increased. CONCLUSION: The renoprotective effect of delayed IPC combined with galectin-9 was superior to IPC alone, through a mechanism related to expansion of regulatory T cells.


Subject(s)
Acute Kidney Injury/prevention & control , Galectins , Ischemic Preconditioning/methods , Reperfusion Injury , T-Lymphocytes, Regulatory/immunology , Acute Kidney Injury/etiology , Acute Kidney Injury/immunology , Animals , Creatinine/blood , Disease Models, Animal , Galectins/metabolism , Galectins/pharmacology , Inflammation/immunology , Inflammation/prevention & control , Kidney/immunology , Kidney/pathology , Kidney Function Tests/methods , Male , Mice , Protective Agents/metabolism , Protective Agents/pharmacology , Reperfusion Injury/complications , Reperfusion Injury/immunology , Reperfusion Injury/prevention & control , Treatment Outcome
14.
Am J Nephrol ; 39(6): 466-75, 2014.
Article in English | MEDLINE | ID: mdl-24854145

ABSTRACT

AIMS: To investigate the impacts of combinatorial atorvastatin (Ator) perioperative administration and mesenchymal stem cell (MSC) implantation on therapeutic effects in the rat experimental acute kidney injury. METHODS: The model of renal ischemia-reperfusion (I/R) injury was induced by the release of bilateral renal pedicle clamps following 45 min of occlusion. Immediately after reperfusion, CM-Dil-labeled MSCs (1 × 10(6) cells) or vehicles only were administered through the carotid artery of the animals pretreated with or without Ator. RESULTS: The combined treatment with Ator and MSCs (Ator+MSCs) markedly reduced the elevated levels of serum creatinine and blood urea nitrogen, as well as the severity of renal damage 24 h after I/R injury. In addition, we also observed inhibition of renal tubular cell apoptosis and promotion of proliferation in the Ator+MSCs group compared with the other groups. Consistent with the improvement in renal function and morphology, Ator pretreatment significantly ameliorated oxidative stress, inhibited inflammation response, and increased the viability of implanted MSCs. With regard to the further mechanism, we found that the expression of Toll-like receptor 4 (TLR4) and high-mobility group box 1, potential mediators of innate immunity, was significantly decreased in the Ator-treated groups. CONCLUSION: Ator treatment may protect the kidney undergoing I/R injury through suppression of TLR4 signaling, creating a better environment for the survival of grafted MSCs. The extra benefit of the Ator+MSCs combined therapy may result from the Ator-mediated inhibition of oxidative stress and inflammation in the ischemic kidney.


Subject(s)
Acute Kidney Injury/metabolism , Graft Survival/drug effects , Heptanoic Acids/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Kidney/drug effects , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/drug effects , Pyrroles/pharmacology , Reperfusion Injury/metabolism , Animals , Atorvastatin , HMGB1 Protein/drug effects , Immunity, Innate/drug effects , Inflammation/metabolism , Kidney/blood supply , Oxidative Stress/drug effects , Rats , Toll-Like Receptor 4/drug effects
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