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  • 1.
    Engström, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Krishnan, K. Syam
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ngyuen, Bidong D.
    Chorell, Erik
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Silver, Jim
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bastidas, Robert J.
    Welch, Matthew D.
    Hultgren, Scott J.
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Valdivia, Raphael H.
    Almqvist, Fredrik
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of Chlamydia trachomatis2015In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 6, no 1, article id e02304-14Article in journal (Refereed)
    Abstract [en]

    In a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Here, by using a visual screen for compounds that affect bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggest that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections.

  • 2.
    Good, James A. D.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Kulén, Martina
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Silver, Jim
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Krishnan, K. Syam
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bahnan, Wael
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Núñez-Otero, Carlos
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Nilsson, Ingela
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wede, Emma
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    de Groot, Esmee
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Thiazolino 2-pyridone amide isosteres as inhibitors of Chlamydia trachomatis infectivity2017In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 22, p. 9393-9399Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis is a global health burden due to its prevalence as a sexually transmitted disease and as the causative agent of the eye infection trachoma. We recently discovered 3-amido thiazolino 2-pyridones which attenuated C. trachomatis infectivity without affecting host cell or commensal bacteria viability. We present here the synthesis and evaluation of nonhydrolyzable amide isosteres based on this class, leading to highly potent 1,2,3-triazole based infectivity inhibitors (EC50 ≤ 20 nM).

  • 3.
    Good, James A. D.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Silver, Jim
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nunez-Otero, Carlos
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bahnan, Wael
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Krishnan, K. Syam
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Salin, Olli
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Engström, Patrik
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Svensson, Richard
    Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden; The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium Sweden, Uppsala University, SE-751 23 Uppsala, Sweden.
    Artursson, Per
    Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden; The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium Sweden, Uppsala University, SE-751 23 Uppsala, Sweden.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 5, p. 2094-2108Article in journal (Refereed)
    Abstract [en]

    The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 <= 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 mu M. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.

  • 4.
    Marwaha, Sania
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Uvell, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Salin, Olli
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindgren, Anders E. G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Silver, Jim
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    N-acylated derivatives of sulfamethoxazole and sulfafurazole inhibit intracellular growth of Chlamydia trachomatis2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 5, p. 2968-2971Article in journal (Refereed)
    Abstract [en]

    Antibacterial compounds with novel modes of action are needed for management of bacterial infections. Here we describe a high-content screen of 9,800 compounds identifying acylated sulfonamides as novel growth inhibitors of the sexually transmitted pathogen Chlamydia trachomatis. The effect was bactericidal and distinct from that of sulfonamide antibiotics, as para-aminobenzoic acid did not reduce efficacy. Chemical inhibitors play an important role in Chlamydia research as probes of potential targets and as drug development starting points.

  • 5.
    Mei, Ya-Fang
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Silver, Jim
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Completely replication-competent adenovirus 11p GFP (RCAd11pGFP) vector with an insertion upstream of the full-length E1 regionArticle in journal (Other academic)
  • 6.
    Mei, Ya-Fang
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wu, Haidong
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hultenby, Kjell
    Silver, Jim
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Complete replication-competent adenovirus 11p vectors with E1 or E3 insertions show improved heat stability2016In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 497, p. 198-210Article in journal (Refereed)
    Abstract [en]

    Conventional adenovirus vectors harboring E1 or E3 deletions followed by the insertion of an exogenous gene show considerably reduced virion stability. Here, we report strategies to generate complete replication-competent Ad11p(RCAd11p) vectors that overcome the above disadvantage. A GFP cassette was successfully introduced either upstream of E1A or in the E3A region. The resulting vectors showed high expression levels of the hexon and E1genes and also strongly induced the cytopathic effect in targeted cells. When harboring oversized genomes, the RCAd11pE1 and RCAd11pE3 vectors showed significantly improved heat stability in comparison to Ad11pwt; of the three, RCAd11pE3 was the most tolerant to heat treatment. Electron microscopy showed that RCAd11pE3, RCAd11pE1, Ad11pwt, and Ad11pE1 Delmanifested dominant, moderate, minimum, or no full virus particles after heat treatment at 47°C for 5 h. Our results demonstrated that both genome size and the insertion site in the viral genome affect virion stability.

  • 7.
    Sandberg, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Papareddy, Praveen
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Silver, Jim
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Replication-competent Ad11p vector (RCAd11p) efficiently transduces and replicates in hormone-refractory metastatic prostate cancer cells2009In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 20, no 4, p. 361-373Article in journal (Refereed)
    Abstract [en]

    Selective replication-competent adenovirus serotype 5 vectors have been used for prostate cancer therapy. Unfortunately, gene transfer is inefficient because hormone-refractory metastatic prostate cancer cells have minimal coxsackievirus-adenovirus receptor expression. Vectors based on species B adenoviruses are attractive tools for use in human gene therapy because the viruses have low seroprevalence and they have efficient transduction capacity. Most species B adenoviruses use ubiquitously expressed complement-regulatory CD46 protein as a cellular receptor. Here we report the transduction efficacy and oncolytic capacity of a replication-competent Ad11p (RCAd11p) vector in human prostate cancer cells. Green fluorescent protein was efficiently expressed in a dose-dependent manner in PC-3 and DU 145 cells derived from metastasis of prostate cancer to bone and brain, respectively. However, transduction was less effective in LNCaP cells derived from prostate cancer metastasis to lymph nodes. The oncolytic capacity of the RCAd11p vector was 100 times higher in PC-3 cells than in the two other cell lines. The oncolysis was independent of the level of expression of p53 in the cells or on the absence of E1B55k expression in the vector. In vivo experiments revealed significant growth inhibition of PC-3 tumors in the xenograft mouse group treated with RCAd11p vector or Ad11pwt in comparison with the untreated control group. Thus, we have demonstrated that RCAd11p vector intrinsically possesses oncolytic properties, which were active in targeting tumor cells. Consequently, the novel RCAd11p vector has great potential for the treatment of incurable metastatic prostate disease.

  • 8.
    Silver, Jim
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Replication-competent adenovirus 11p vector as a new oncolytic agent2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human adenoviruses (Ads) as vectors have been studied for cancer gene therapy for several decades due to their ability to shut down host cell replication and lyse tumour cells. Ad5 of species C is commonly used as a replication-defective or a replication-competent vector. However, many tumour cells are relatively refractory to infection by Ad5 since the cells lack the viral receptor CAR. Thus, species B Ads are becoming more important as alternative vectors since they use CD46 as primary receptor, the expression of which is up-regulated on many tumour cell surfaces, and they also have low seroprevalence in humans. Although Ad3, Ad7, Ad11 and Ad35 have been altered to become replication-defective vectors, investigations based on replicating adenovirus vectors are still warranted.  

    The major aim of this thesis has been to characterize the transduction efficacy and oncolytic effect of the replication-competent adenovirus 11pGFP vector (RCAd11pGFP) in human solid tumour cell lines. Evaluation of the vector would ultimately help us to understand whether the tumour cells affect virus replication and whether the vector replicates differently in tumour cells and in untransformed diploid cells, and would eventually lead to development of more potent oncolytic adenoviruses for treatment of human cancers.

    The Ad11-based vector RCAd11pGFP consists of the entire Ad11p genome with a green fluorescence protein (GFP) expression cassette inserted. RCAd11pGFP shows all the characteristics of the wild-type virus and expresses GFP in cells four hours p.i. Antisera raised against Ad11p virions and hexons were able to neutralize RCAd11pGFP infection but antiserum raised against the Ad11p fibre knob could not. The infection is reduced by 90% but the fibre knob antiserum cannot completely block virus infection. Initial screening of the infection capacity of five wild-type adenoviruses in four colon cancer cell lines revealed that Ad11p, Ad11a and Ad35 of species B, showed similar replication kinetics but Ad5 showed delayed onset of virus replication in comparison to species B Ads. These data support the use of Ad11p as an alternative vector for treatment of colon cancer.

    The transduction efficiency of RCAd11pGFP in colon cancer and prostate cancer cell lines was studied using flow cytometry assay (FACS), and this showed that the cytolytic effect was not always in accordance with GFP expression. Toxicity assay and virus one-step replication assay showed that RCAd11pGFP replicates in highly tumorigenic cell lines (HT29, T84 and PC-3) to a greater extent than less tumorigenic cell lines (LS174T, HCT-8, DU145 and LNCaP cells), even though the latter showed relatively high GFP expression. This initial finding led to the subsequent discovery of CEACAM-family molecules, which were highly expressed in HT29 and T84 cells. Interestingly, the Ad5 wild-type virus did not manifest the same tumour-specific replication that RCAd11pGFP did in the cell lines studied.

    Furthermore, we investigated the influence of tumour markers for RCAd11pGFP replication in colon cancer cells. A double-staining FACS assay for detecting members of CEACAM-family molecules was established and we found that the levels of CEACAM6 were up-regulated in the cells infected by RCAd11pGFP or Ad11pwt relative to uninfected cells. However, this virus replication could not be suppressed by CEACEA6 siRNA. Our results indicate that several tumour markers or factors might be involved in promoting propagation of the virus.

    In vivo experiments showed significant growth inhibition of T84 and HT-29 tumours in xenograft mice treated with either RCAd11pGFP or Ad11pwt, compared to untreated controls. Furthermore, the role of the anti-tumour effect of RCAd11pGFP was also confirmed in PC3 prostate tumours in BALB/c mice.

    In conclusion, the novel RCAd11pGFP vector was shown to have an anti-tumour effect in vitro and in vivo. This tumour-killing effect could be enhanced in highly tumorogenic cells through virus replication. Consequently, RCAd11p may lead to development of a more potent and useful vector for human cancer therapy.  

  • 9.
    Silver, Jim
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Islam, Bakhtiar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Replication-competent adenovirus 11p GFP vector (RCAd11pGFP) enhances CEACAM6 expression in colon cancer cellsManuscript (preprint) (Other academic)
  • 10.
    Silver, Jim
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Transduction and oncolytic profile of a potent replication-competent adenovirus 11p vector (RCAd11pGFP) in colon carcinoma cells2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e17532-Article in journal (Refereed)
    Abstract [en]

    Replication-competent adenovirus type 5 (Ad5) vectors promise to be more efficient gene delivery vehicles than their replication-deficient counterparts, and chimeric Ad5 vectors that are capable of targeting CD46 are more effective than Ad5 vectors with native fibers. Although several strategies have been used to improve gene transduction and oncolysis, either by modifying their tropism or enhancing their replication capacity, some tumor cells are still relatively refractory to infection by chimeric Ad5. The oncolytic effects of the vectors are apparent in certain tumors but not in others. Here, we report the biological and oncolytic profiles of a replication-competent adenovirus 11p vector (RCAd11pGFP) in colon carcinoma cells. CD46 was abundantly expressed in all cells studied; however, the transduction efficiency of RCAd11pGFP varied. RCAd11pGFP efficiently transduced HT-29, HCT-8, and LS174T cells, but it transduced T84 cells, derived from a colon cancer metastasis in the lung, less efficiently. Interestingly, RCAd11p replicated more rapidly in the T84 cells than in HCT-8 and LS174T cells and as rapidly as in HT-29 cells. Cell toxicity and proliferation assays indicated that RCAd11pGFP had the highest cell-killing activities in HT29 and T84 cells, the latter of which also expressed the highest levels of glycoproteins of the carcinoma embryonic antigen (CEA) family. In vivo experiments showed significant growth inhibition of T84 and HT-29 tumors in xenograft mice treated with either RCAd11pGFP or Ad11pwt compared to untreated controls. Thus, RCAd11pGFP has a potent cytotoxic effect on colon carcinoma cells.

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