Genomes and Genes
Gene Symbol: Ifnb1
Description: interferon beta 1, fibroblast
Alias: IFN-beta, IFNB, Ifb, interferon beta
- Deonarain R, Verma A, Porter A, Gewert D, Platanias L, Fish E. Critical roles for IFN-beta in lymphoid development, myelopoiesis, and tumor development: links to tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 2003;100:13453-8 pubmed..Taken altogether, our data suggest that, in addition to the direct growth-inhibitory effects on tumor cells, IFN-beta is required during different stages of maturation in the development of the immune system. ..
- Freudenberg M, Merlin T, Kalis C, Chvatchko Y, Stübig H, Galanos C. Cutting edge: a murine, IL-12-independent pathway of IFN-gamma induction by gram-negative bacteria based on STAT4 activation by Type I IFN and IL-18 signaling. J Immunol. 2002;169:1665-8 pubmed..This pathway participates in the induction of IFN-gamma by Gram-negative bacteria and is therefore expected to play a role whenever IFN-alpha or IFN-beta and IL-18 are produced concomitantly during bacterial, viral, or other infections. ..
- Hirotani T, Yamamoto M, Kumagai Y, Uematsu S, Kawase I, Takeuchi O, et al. Regulation of lipopolysaccharide-inducible genes by MyD88 and Toll/IL-1 domain containing adaptor inducing IFN-beta. Biochem Biophys Res Commun. 2005;328:383-92 pubmed..Genes known to be induced by type I interferons were simply dependent on TRIF for their expression. Taken together, MyD88 and TRIF play both redundant and distinct roles in LPS-induced gene expression. ..
- Blanc M, Hsieh W, Robertson K, Watterson S, Shui G, Lacaze P, et al. Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis. PLoS Biol. 2011;9:e1000598 pubmed publisher..These findings bring a new link between sterol metabolism and interferon antiviral response and support the idea of using host metabolic modifiers of innate immunity as a potential antiviral strategy. ..
- Weiss G, Maaetoft Udsen K, Stifter S, Hertzog P, Goriely S, Thomsen A, et al. MyD88 drives the IFN-? response to Lactobacillus acidophilus in dendritic cells through a mechanism involving IRF1, IRF3, and IRF7. J Immunol. 2012;189:2860-8 pubmed publisher..acidophilus induces IFN-? independently of the receptors typically used by bacteria, as it requires MyD88, Syk, and PI3K signaling and phagosomal processing to activate IRF1 and IRF3/IRF7 and thereby the release of IFN-?. ..
- Mattner J, Wandersee Steinhäuser A, Pahl A, Rollinghoff M, Majeau G, Hochman P, et al. Protection against progressive leishmaniasis by IFN-beta. J Immunol. 2004;172:7574-82 pubmed..These results identify IFN-beta as a novel cytokine with a strong, dose-dependent protective effect against progressive cutaneous leishmaniasis that results from IL-12- and STAT4-dependent as well as -independent events. ..
- Mancuso G, Midiri A, Biondo C, Beninati C, Zummo S, Galbo R, et al. Type I IFN signaling is crucial for host resistance against different species of pathogenic bacteria. J Immunol. 2007;178:3126-33 pubmed..These data may be useful to devise alternative strategies to treat bacterial infections. ..
- Schleicher U, Liese J, Knippertz I, Kurzmann C, Hesse A, Heit A, et al. NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs. J Exp Med. 2007;204:893-906 pubmed
- Chen M, Chen G, Nie H, Zhang X, Niu X, Zang Y, et al. Regulatory effects of IFN-beta on production of osteopontin and IL-17 by CD4+ T Cells in MS. Eur J Immunol. 2009;39:2525-36 pubmed publisher..This study provides new insights into the mechanism of action of IFN-beta in the treatment of MS. ..
- Mancuso G, Gambuzza M, Midiri A, Biondo C, Papasergi S, Akira S, et al. Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells. Nat Immunol. 2009;10:587-94 pubmed publisher..Thus, this cell type-specific recognition pathway links lysosomal recognition of bacterial RNA with a robust, host-protective interferon response. ..
- Zwaferink H, Stockinger S, Hazemi P, Lemmens Gruber R, Decker T. IFN-beta increases listeriolysin O-induced membrane permeabilization and death of macrophages. J Immunol. 2008;180:4116-23 pubmed..Key lipogenesis enzymes were suppressed in IFN-beta-treated cells, which may exacerbate the membrane damage caused by LLO. ..
- Lienenklaus S, Cornitescu M, Zietara N, Łyszkiewicz M, Gekara N, Jabłónska J, et al. Novel reporter mouse reveals constitutive and inflammatory expression of IFN-beta in vivo. J Immunol. 2009;183:3229-36 pubmed publisher..This relatively high constitutive expression was controlled by the NF Aire and might influence induction of tolerance or T cell development. ..
- Kaplan A, Ma J, Kyme P, Wolf A, Becker C, Tseng C, et al. Failure to induce IFN-? production during Staphylococcus aureus infection contributes to pathogenicity. J Immunol. 2012;189:4537-45 pubmed publisher..aureus infection (in vitro and in vivo) was protective. Together, the data demonstrate that failure to induce IFN-? production during S. aureus infection contributes to pathogenicity. ..
- Erlandsson L, Blumenthal R, Eloranta M, Engel H, Alm G, Weiss S, et al. Interferon-beta is required for interferon-alpha production in mouse fibroblasts. Curr Biol. 1998;8:223-6 pubmed..These results imply a unique role for IFN-beta in the induction of type I interferons in peripheral tissues. ..
- Honda K, Yanai H, Takaoka A, Taniguchi T. Regulation of the type I IFN induction: a current view. Int Immunol. 2005;17:1367-78 pubmed..The understanding of the regulatory mechanisms of IFN-alpha/beta gene induction by TLRs and viruses is an emerging theme, for which much new insight has been gained over the past few years. ..
- Chang E, Guo B, Doyle S, Cheng G. Cutting edge: involvement of the type I IFN production and signaling pathway in lipopolysaccharide-induced IL-10 production. J Immunol. 2007;178:6705-9 pubmed..Our findings suggest a novel anti-inflammatory role for the type I IFN production and signaling pathway in regulating LPS response in bone marrow-derived macrophages. ..
- Berenson L, Ota N, Murphy K. Issues in T-helper 1 development--resolved and unresolved. Immunol Rev. 2004;202:157-74 pubmed..None of these areas is static or resolved fully, and they likely will remain topics of rapid progress. ..
- de Weerd N, Vivian J, Nguyen T, Mangan N, Gould J, Braniff S, et al. Structural basis of a unique interferon-? signaling axis mediated via the receptor IFNAR1. Nat Immunol. 2013;14:901-7 pubmed publisher..Thus, we provide a molecular basis for understanding specific functions of IFN-?. ..
- Johansson A, Nakken B, Sundler M, Lindqvist A, Johannesson M, ALARCON RIQUELME M, et al. The genetic control of sialadenitis versus arthritis in a NOD.QxB10.Q F2 cross. Eur J Immunol. 2002;32:243-50 pubmed..The genetic control of sialadenitis seemed to be unique in comparison to diabetes and arthritis, as no loci associated with these diseases have been identified at the same location. ..
- Deonarain R, Alcami A, Alexiou M, Dallman M, Gewert D, Porter A. Impaired antiviral response and alpha/beta interferon induction in mice lacking beta interferon. J Virol. 2000;74:3404-9 pubmed..Furthermore, in cultured embryo fibroblasts, viral induction of alpha interferon and of 2-5A synthetase genes is impaired. We also show that beta interferon does not prime its own expression. ..
- Henry T, Brotcke A, Weiss D, Thompson L, Monack D. Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J Exp Med. 2007;204:987-94 pubmed..This connection underscores the importance of the cytosolic recognition of pathogens and highlights how multiple innate immunity pathways interact before commitment to critical host responses...
- Richez C, Yasuda K, Watkins A, Akira S, Lafyatis R, VAN SEVENTER J, et al. TLR4 ligands induce IFN-alpha production by mouse conventional dendritic cells and human monocytes after IFN-beta priming. J Immunol. 2009;182:820-8 pubmed..This data demonstrates a novel pathway for IFN-alpha production by cDCs and provides one possible explanation for how bacterial infection might precipitate disease flares in SLE. ..
- Strobl B, Bubic I, Bruns U, Steinborn R, Lajko R, Kolbe T, et al. Novel functions of tyrosine kinase 2 in the antiviral defense against murine cytomegalovirus. J Immunol. 2005;175:4000-8 pubmed..In addition to the established role of Tyk2 as an amplifier of Jak/Stat signaling upon IFN-alphabeta stimulation, we provide evidence for a novel role of Tyk2 as a modifier of host responses. ..
- Feng H, Zhang D, Palliser D, Zhu P, Cai S, Schlesinger A, et al. Listeria-infected myeloid dendritic cells produce IFN-beta, priming T cell activation. J Immunol. 2005;175:421-32 pubmed..Exposure to high concentrations of IFN-beta sensitizes naive T cells for Ag-dependent activation. ..
- Honda K, Mizutani T, Taniguchi T. Negative regulation of IFN-alpha/beta signaling by IFN regulatory factor 2 for homeostatic development of dendritic cells. Proc Natl Acad Sci U S A. 2004;101:2416-21 pubmed
- Karaghiosoff M, Steinborn R, Kovarik P, Kriegshäuser G, Baccarini M, Donabauer B, et al. Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nat Immunol. 2003;4:471-7 pubmed..IFN-beta-null but not STAT1-null mice were also resistant to high dose LPS treatment. Together, these data suggest that Tyk2 and IFN-beta are essential effectors in LPS induced lethality. ..
- Gleason C, Ordureau A, Gourlay R, Arthur J, Cohen P. Polyubiquitin binding to optineurin is required for optimal activation of TANK-binding kinase 1 and production of interferon ?. J Biol Chem. 2011;286:35663-74 pubmed publisher..In conclusion, our results suggest that OPTN binds to polyubiquitylated species formed in response to LPS and poly(I:C), enhancing the activation of TBK1 that is required for optimal phosphorylation of IRF3 and production of IFN?. ..
- Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005;434:772-7 pubmed..Thus, all elements of IFN responses, whether the systemic production of IFN in innate immunity or the local action of IFN from plasmacytoid dendritic cells in adaptive immunity, are under the control of IRF-7. ..
- Schiavoni G, Mauri C, Carlei D, Belardelli F, Pastoris M, Proietti E. Type I IFN protects permissive macrophages from Legionella pneumophila infection through an IFN-gamma-independent pathway. J Immunol. 2004;173:1266-75 pubmed..pneumophila infection in mouse models of susceptible macrophages and suggest the existence of different pathways for the control of intracellular bacteria in macrophages. ..
- Matheu V, Treschow A, Navikas V, Issazadeh Navikas S. Upregulation of B7 molecules (CD80 and CD86) and exacerbated eosinophilic pulmonary inflammatory response in mice lacking the IFN-beta gene. J Allergy Clin Immunol. 2003;111:550-7 pubmed..We assessed whether deletion of the gene encoding IFN-beta (IFNB) with knockout mice participated in the development of allergic response in ovalbumin (OVA)-sensitized and OVA-..
- Stockinger S, Materna T, Stoiber D, Bayr L, Steinborn R, Kolbe T, et al. Production of type I IFN sensitizes macrophages to cell death induced by Listeria monocytogenes. J Immunol. 2002;169:6522-9 pubmed..The data stress the importance of type I IFN for the course of infections with intracellular bacteria and suggest that factors other than listeriolysin O contribute to macrophage death during Listeria infection. ..
- O RIORDAN M, Yi C, Gonzales R, Lee K, Portnoy D. Innate recognition of bacteria by a macrophage cytosolic surveillance pathway. Proc Natl Acad Sci U S A. 2002;99:13861-6 pubmed..of Gram-positive and Gram-negative bacterial products by this surveillance system results in transcription of the ifnb gene...
- Kim J, Kim T, Lee H, Nikapitiya C, Uddin M, Park M, et al. Rubicon Modulates Antiviral Type I Interferon (IFN) Signaling by Targeting IFN Regulatory Factor 3 Dimerization. J Virol. 2017;91: pubmed publisher..The results of this study will increase our understanding of the role of negative-feedback mechanisms that regulate type I IFN signaling and maintain immune homeostasis. ..
- Baccarella A, Fontana M, Chen E, Kim C. Toll-like receptor 7 mediates early innate immune responses to malaria. Infect Immun. 2013;81:4431-42 pubmed publisher..Our findings indicate that TLR7 plays a central role in early immune activation during malaria infection, whereas TLR7 and TLR9 contribute combinatorially to immune responses as infection progresses. ..
- Medrano R, Catani J, Ribeiro A, Tomaz S, Merkel C, Costanzi Strauss E, et al. Vaccination using melanoma cells treated with p19arf and interferon beta gene transfer in a mouse model: a novel combination for cancer immunotherapy. Cancer Immunol Immunother. 2016;65:371-82 pubmed publisherPreviously, we combined p19(Arf) (Cdkn2a, tumor suppressor protein) and interferon beta (IFN-Î², immunomodulatory cytokine) gene transfer in order to enhance cell death in a murine model of melanoma...
- Mohammadzadeh A, Pourfathollah A, Shahrokhi S, Fallah A, Tahoori M, Amari A, et al. Evaluation of AD-MSC (adipose-derived mesenchymal stem cells) as a vehicle for IFN-? delivery in experimental autoimmune encephalomyelitis. Clin Immunol. 2016;169:98-106 pubmed publisher..the effects of genetically modified adipose-derived mesenchymal stem cells (AD-MSCs) expressing murine interferon beta (MSCs-VP/IFN-?) on the animal model of MS, experimental autoimmune encephalomyelitis (EAE)...
- Takashima K, Takeda Y, Oshiumi H, Shime H, Okabe M, Ikawa M, et al. STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation. Biochem Biophys Res Commun. 2016;478:1764-71 pubmed publisher..Our data show that STING induces tumor cytotoxicity by NK cells through tumor and host immune cell network to contribute to innate surveillance and suppression of tumors in vivo. ..
- Vodjdani G, Le Roscouet D, Horth M, Perucca Lostanlen D, Gallien C, Doly J. Structure of mouse interferon-beta cDNA clones: sequence rearrangements in a cloned cDNA. Biochem Int. 1985;10:495-505 pubmed..A mechanism for the rearrangement events during cDNA synthesis is proposed. A chromosomal DNA fragment hybridizing to cDNA 2939 was identified by screening a mouse genomic library. ..
- Zhao X, Zhu H, Yu J, Li H, Ge J, Chen W. c-Cbl-mediated ubiquitination of IRF3 negatively regulates IFN-? production and cellular antiviral response. Cell Signal. 2016;28:1683-93 pubmed publisher..Therefore, our findings suggest that c-Cbl negatively regulates IFN-? signaling and cellular antiviral response by promoting IRF3 ubiquitination and degradation, providing a new mechanism for control of type I interferon induction. ..
- Fejer G, Drechsel L, Liese J, Schleicher U, Ruzsics Z, Imelli N, et al. Key role of splenic myeloid DCs in the IFN-alphabeta response to adenoviruses in vivo. PLoS Pathog. 2008;4:e1000208 pubmed publisher..The hypersensitivity to components of the microbial flora and invading pathogens may in part explain the toxic side effects of adenoviral gene therapy and contribute to the pathogenesis of adenoviral disease. ..
- Gregorio J, Meller S, Conrad C, Di Nardo A, Homey B, Lauerma A, et al. Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons. J Exp Med. 2010;207:2921-30 pubmed publisher..These data uncover a new role of pDCs in sensing tissue damage and promoting wound repair at skin surfaces. ..
- Proença Módena J, Hyde J, Sesti Costa R, Lucas T, Pinto A, Richner J, et al. Interferon-Regulatory Factor 5-Dependent Signaling Restricts Orthobunyavirus Dissemination to the Central Nervous System. J Virol. 2016;90:189-205 pubmed publisher..We demonstrate an important role for IRF-5 in preventing neuroinvasion and the ensuing encephalitis caused by OROV and LACV. ..
- Chessler A, Caradonna K, Da dara A, Burleigh B. Type I interferons increase host susceptibility to Trypanosoma cruzi infection. Infect Immun. 2011;79:2112-9 pubmed publisher..These findings are consistent with a growing theme in the microbial pathogenesis field in which type I IFNs can be detrimental to the host in a variety of nonviral pathogen infection models. ..
- Detje C, Lienenklaus S, Chhatbar C, Spanier J, Prajeeth C, Soldner C, et al. Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon Beta producers that protect from lethal encephalitis. J Virol. 2015;89:2731-8 pubmed publisher..Our results are surprising because in other infection models astrocytes have not yet been identified as major type I IFN producers. ..
- Koerner I, Kochs G, Kalinke U, Weiss S, Staeheli P. Protective role of beta interferon in host defense against influenza A virus. J Virol. 2007;81:2025-30 pubmed
- Härle P, Cull V, Agbaga M, Silverman R, Williams B, James C, et al. Differential effect of murine alpha/beta interferon transgenes on antagonization of herpes simplex virus type 1 replication. J Virol. 2002;76:6558-67 pubmed..These results suggest that the predominant IFN-mediated, antiviral pathway during HSV-1 infection taken by IFN-alpha/beta in L929 cells utilizes PKR. ..
- Ishikawa H, Awano N, Fukui T, Sasaki H, Kyuwa S. The protective effects of lactoferrin against murine norovirus infection through inhibition of both viral attachment and replication. Biochem Biophys Res Commun. 2013;434:791-6 pubmed publisher..The present results provide evidence that lactoferrin may be useful as a preventive and/or therapeutic anti-norovirus agent. ..
- Kang T, Basu S, Zhang L, Thomas K, Vogel S, Baillie L, et al. Bacillus anthracis spores and lethal toxin induce IL-1beta via functionally distinct signaling pathways. Eur J Immunol. 2008;38:1574-84 pubmed publisher..Thus different components of the same bacterium each induce IL-1beta by distinct signaling pathways. Whereas the spore-induced IL-1beta limits BA infection, LT-induced IL-1beta enables BA to escape host defenses...
- Núñez N, Andreani V, Crespo M, Nocera D, Breser M, Moron G, et al. IFN? produced by TLR4-activated tumor cells is involved in improving the antitumoral immune response. Cancer Res. 2012;72:592-603 pubmed publisher..Together, our findings show that tumor cells can be induced through the TLR4 pathway to produce IFN and positively contribute to the antitumoral immune response. ..
- Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature. 2002;416:744-9 pubmed..Our study places the IFN-beta system in a new context, and may offer a molecular basis for the treatment of bone diseases. ..
- Raghuraman G, Geng Y, Wang C. IFN-beta-mediated up-regulation of CD1d in bacteria-infected APCs. J Immunol. 2006;177:7841-8 pubmed..Taken together, these data support a role for early IFN-beta-mediated up-regulation of CD1d in NKT cell activation during infection. ..
- Antoniak S, Tatsumi K, Bode M, Vanja S, Williams J, Mackman N. Protease-Activated Receptor 1 Enhances Poly I:C Induction of the Antiviral Response in Macrophages and Mice. J Innate Immun. 2017;9:181-192 pubmed publisher..These studies suggest that thrombin activation of PAR-1 contributes to the antiviral response in mice. ..
- Burdeinick Kerr R, Wind J, Griffin D. Synergistic roles of antibody and interferon in noncytolytic clearance of Sindbis virus from different regions of the central nervous system. J Virol. 2007;81:5628-36 pubmed
- Wilden H, Fournier P, Zawatzky R, Schirrmacher V. Expression of RIG-I, IRF3, IFN-beta and IRF7 determines resistance or susceptibility of cells to infection by Newcastle Disease Virus. Int J Oncol. 2009;34:971-82 pubmed..A strong expression of these genes can explain the resistance of normal cells to NDV infection and a weak antiviral gene expression the broad susceptibility of tumor cells. ..
- Zhang X, Ye Z, Pei Y, Qiu G, Wang Q, Xu Y, et al. Neddylation is required for herpes simplex virus type I (HSV-1)-induced early phase interferon-beta production. Cell Mol Immunol. 2016;13:578-83 pubmed publisher..Thus, neddylation contributes to HSV-1-induced early phase IFN-? production through, at least partially, promoting NF-?B activation. ..
- Lee Y, Hyung S, Jung H, Kim H, Staerk J, Constantinescu S, et al. The ubiquitin-mediated degradation of Jak1 modulates osteoclastogenesis by limiting interferon-beta-induced inhibitory signaling. Blood. 2008;111:885-93 pubmed..These data suggest that the regulation of Jak1 expression during osteoclast differentiation might serve as an intrinsic mechanism that determines osteoclast lineage commitment by modulating the negative regulation by IFN-beta. ..
- Tanaka N, Taniguchi T. Cytokine gene regulation: regulatory cis-elements and DNA binding factors involved in the interferon system. Adv Immunol. 1992;52:263-81 pubmed
- Guo H, König R, Deng M, Riess M, Mo J, Zhang L, et al. NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses. Cell Host Microbe. 2016;19:515-528 pubmed publisher..Accordingly, Nlrx1(-/-) mice infected with DNA viruses exhibit enhanced innate immunity and reduced viral load. Thus, NLRX1 is a negative regulator of the host innate immune response to HIV-1 and DNA viruses. ..
- Dai P, Wang W, Cao H, Avogadri F, Dai L, Drexler I, et al. Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. PLoS Pathog. 2014;10:e1003989 pubmed publisher..We present evidence that vaccinia virulence factors E3 and N1 inhibit the activation of IRF3 and the induction of IFNB gene in MVA-infected cDCs.
- Migliorini A, Angelotti M, Mulay S, Kulkarni O, Demleitner J, Dietrich A, et al. The antiviral cytokines IFN-? and IFN-? modulate parietal epithelial cells and promote podocyte loss: implications for IFN toxicity, viral glomerulonephritis, and glomerular regeneration. Am J Pathol. 2013;183:431-40 pubmed publisher
- Price G, Gaszewska Mastarlarz A, Moskophidis D. The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice. J Virol. 2000;74:3996-4003 pubmed..However, IFN-alpha/beta seems to be a valid factor in determining tissue tropism and replicative rates of highly virulent influenza virus strains as reported previously by others, and this aspect is discussed here. ..
- Johansson M, Taylor M, Jagodic M, Tus K, Schatzle J, Wakeland E, et al. Mapping of quantitative trait loci determining NK cell-mediated resistance to MHC class I-deficient bone marrow grafts in perforin-deficient mice. J Immunol. 2006;177:7923-9 pubmed..This study describes the first important step toward identifying BM graft resistance gene(s). ..
- Lake F, Noble P, Henson P, Riches D. Functional switching of macrophage responses to tumor necrosis factor-alpha (TNF alpha) by interferons. Implications for the pleiotropic activities of TNF alpha. J Clin Invest. 1994;93:1661-9 pubmed
- Vigon I, Florindo C, Fichelson S, Guenet J, Mattei M, Souyri M, et al. Characterization of the murine Mpl proto-oncogene, a member of the hematopoietic cytokine receptor family: molecular cloning, chromosomal location and evidence for a function in cell growth. Oncogene. 1993;8:2607-15 pubmed..This demonstrated that the cytoplasmic Mpl domain is most probably implicated in proliferative signal transduction. ..
- Ryman K, Meier K, Gardner C, Adegboyega P, Klimstra W. Non-pathogenic Sindbis virus causes hemorrhagic fever in the absence of alpha/beta and gamma interferons. Virology. 2007;368:273-85 pubmed