Richard Bucala

Bio: Richard Bucala is an academic researcher from Yale University. The author has contributed to research in topics: Macrophage migration inhibitory factor & Cytokine. The author has an hindex of 119, co-authored 595 publications receiving 54607 citations. Previous affiliations of Richard Bucala include École Polytechnique Fédérale de Lausanne & Rockefeller University.

Macrophage migration inhibitory factor enhances Pseudomonas aeruginosa biofilm formation, potentially contributing to cystic fibrosis pathogenesis.

Abstract: Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator that we have previously shown to be associated with an aggressive clinical phenotype in cystic fibrosis. It possesses unique tautomerase enzymatic activity. However, to date, no human-derived substrate has been identified that has the capacity to interact with this cytokine's unique tautomerase activity. This led us to hypothesize that MIF may have the capacity to interact with external substrates. We describe for the first time how Pseudomonas aeruginosa can utilize human recombinant MIF (rMIF) to significantly (P < 0.01) enhance its endogenous biofilm formation. Our in vivo studies demonstrate that utilizing a small-molecular-weight inhibitor targeting MIF's tautomerase activity (SCD-19) significantly reduces the inflammatory response in a murine pulmonary chronic P. aeruginosa model. In addition, we show that in in vitro experiments, pretreatment of P. aeruginosa with rMIF is associated with reduced bacterial killing by tobramycin. Our novel findings support the concept of an anti-MIF strategy that targets this enzymatic activity as a potential future antibacterial therapeutic approach.-Tynan, A., Mawhinney, L., Armstrong, M. E., O'Reilly, C., Kennedy, S., Caraher, E., Julicher, K., O'Dwyer, D., Maher, L., Schaffer, K., Fabre, A., McKone, E. F., Leng, L., Bucala, R., Bernhagen, J., Cooke, G., Donnelly, S. C. Macrophage migration inhibitory factor enhances Pseudomonas aeruginosa biofilm formation, potentially contributing to cystic fibrosis pathogenesis.

Cloning and chromosomal characterization of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 gene (PFKFB3, iPFK2).

Abstract: PFKFB (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) is a bifunctional enzyme that regulates the steady-state concentration of fructose-2,6-bisphosphate, which is a potent activator of the key regulatory enzyme of glycolysis, phosphofructokinase. PFKFB3 (iPFK2) is one of four tissue-specific PFKFB isozymes that have been identified to date. PFKFB3 also has been implicated in the high glycolytic rate of cancer cells that occurs despite adequate oxygen, a phenomenon known as the Warburg effect. We have isolated and characterized the human PFKFB3 genomic sequence, which spans a region of 32.5 kb and which has a single chromosomal locus. Determination of the exon-intron splice junctions established that PFKFB3 is encoded by 19 exons of which only 15 are normally expressed. Exon sizes range between 23 and 208 bp, the largest intron is 10,286 bp long. The full-length human PFKFB3 open reading frame is 4,675 bp long and encodes a 590 aa protein with a predicted molecular weight of 66.9 kDa and an isoelectric point of 8.64. Fluorescence in situ hybridization analysis localized the human PFKFB3 gene to chromosome 10p15.3-p15.2, and its locus is 3 million bp centromeric to PFKP, the platelet-type phosphofructokinase. PFKFB3 has been shown to be abundantly expressed in human tumors and its expression linked to long-standing observations concerning the apparent coupling of enhanced glycolysis and cell proliferation.

Macrophage migration inhibitory factor exerts pro-proliferative and anti-apoptotic effects via CD74 in murine hepatocellular carcinoma.

Abstract: Background and purpose Macrophage migration inhibitory factor (MIF) is an inflammatory and chemokine-like protein expressed in different inflammatory diseases as well as solid tumours. CD74 - as the cognate MIF receptor - was identified as an important target of MIF. We here analysed the role of MIF and CD74 in the progression of hepatocellular carcinoma (HCC) in vitro and in vivo. Experimental approach Multilocular HCC was induced using the diethylnitrosamine/carbon tetrachloride (DEN/CCl4 ) model in hepatocyte-specific Mif knockout (Mif Δhep ), Cd74-deficient, and control mice. Tumour burden was compared between the genotypes. MIF, CD74 and Ki67 expression were investigated in tumour and surrounding tissue. In vitro, the impact of the MIF/CD74 axis on the proliferative and apoptotic behaviour of hepatoma cells and respective signaling pathways was assessed after treatment with MIF and anti-CD74 antibodies. Key results DEN/CCl4 treatment of Mif Δhep mice resulted in reduced tumour burden and diminished proliferation capacity within tumour tissue. In vitro, MIF stimulated the proliferation of Hepa 1-6 and HepG2 cells, inhibited therapy-induced cell death and induced ERK activation. The investigated effects could be reversed using a neutralizing anti-CD74 antibody, and Cd74-/- mice developed fewer tumours associated with decreased proliferation rates. Conclusion and implications In this study, we identified a pro-tumorigenic role of MIF during proliferation and therapy-induced apoptosis of HCC cells. Our study implicates that these effects are mediated via the MIF cognate receptor CD74. In conclusion, the inhibition of the MIF/CD74 axis could represent a promising target with regard to prospective HCC-directed pharmacological therapies.

Selective preservation of bone marrow mature recirculating but not marginal zone B cells in murine models of chronic inflammation.

Abstract: Inflammation promotes granulopoiesis over B lymphopoiesis in the bone marrow (BM). We studied B cell homeostasis in two murine models of T cell mediated chronic inflammation, namely calreticulin-deficient fetal liver chimeras (FLC), which develop severe blepharitis and alopecia due to T cell hyper responsiveness, and inflammatory bowel disease (IBD) caused by injection of CD4+ naive T cells into lymphopenic mice. We show herein that despite the severe depletion of B cell progenitors during chronic, peripheral T cell-mediated inflammation, the population of BM mature recirculating B cells is unaffected. These B cells are poised to differentiate to plasma cells in response to blood borne pathogens, in an analogous fashion to non-recirculating marginal zone (MZ) B cells in the spleen. MZ B cells nevertheless differentiate more efficiently to plasma cells upon polyclonal stimulation by Toll-like receptor (TLR) ligands, and are depleted during chronic T cell mediated inflammation in vivo. The preservation of mature B cells in the BM is associated with increased concentration of macrophage migration inhibitory factor (MIF) in serum and BM plasma. MIF produced by perivascular dendritic cells (DC) in the BM provides a crucial survival signal for recirculating B cells, and mice treated with a MIF inhibitor during inflammation showed significantly reduced mature B cells in the BM. These data indicate that MIF secretion by perivascular DC may promote the survival of the recirculating B cell pool to ensure responsiveness to blood borne microbes despite loss of the MZ B cell pool that accompanies depressed lymphopoiesis during inflammation.

I and i

Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

Multilineage Potential of Adult Human Mesenchymal Stem Cells

Abstract: Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。