Rapid expression and purification of the hepatitis delta virus antigen using the methylotropic yeast Pichia pastoris

Objective: Patients with dual hepatitis B (HBV) and hepatitis D (HDV) virus infection are at an increased risk of progression to liver cirrhosis and hepatocellular carcinoma than patients with a single viral infection. Treatment of viral hepatitis due to dual HBV/HDV infection represents a challenge. Currently there is no vaccine against HDV. Recombinant production of HDV antigen (HDAg) is the first step towards a potential vaccine candidate and the development of assays for HDV detection. Results: This study demonstrates the expression of one HDAg isoform, S-HDAg, in Pichia pastoris. A recombinant vector carrying a tagged gene encoding S-HDAg under the control of the methanol-inducible promoter AOX1 was designed and integrated into P. pastoris X33. The protein, which was purified using a Ni2+ affinity column and eluted at 100-150 mM imidazole, has potential as a recombinant antigen for further study

Ceacam1 separates graft-versus-host-disease from graft-versus-tumor activity after experimental allogeneic bone marrow transplantation.

BACKGROUND: Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models. METHODS: We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin α(4)β(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells. CONCLUSIONS: We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation

PARP14 promotes the warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation

Most tumour cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and evade apoptosis. Intriguingly, the molecular mechanisms that link the Warburg effect with the suppression of apoptosis are not well understood. In this study, using loss-of-function studies in vitro and in vivo, we show that the anti-apoptotic protein poly(ADP-ribose) polymerase (PARP)14 promotes aerobic glycolysis in human hepatocellular carcinoma (HCC) by maintaining low activity of the pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Notably, PARP14 is highly expressed in HCC primary tumours and associated with poor patient prognosis. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. Moreover, targeting PARP14 enhances the sensitization of HCC cells to anti-HCC agents. Our findings indicate that the PARP14-JNK1-PKM2 regulatory axis is an important determinant for the Warburg effect in tumour cells and provide a mechanistic link between apoptosis and metabolism

Combination of the W boson polarization measurements in top quark decays using ATLAS and CMS data at \sqrt{s} = 8 TeV

The combination of measurements of the W boson polarization in top quark decays performed by the ATLAS and CMS collaborations is presented. The measurements are based on proton-proton collision data produced at the LHC at a centre-of-mass energy of 8 TeV, and corresponding to an integrated luminosity of about 20 fb^{-1} for each experiment. The measurements used events containing one lepton and having different jet multiplicities in the final state. The results are quoted as fractions of W bosons with longitudinal (F_{0}), left-handed (F_{L}), or right-handed (F_{R}) polarizations. The resulting combined measurements of the polarization fractions are F0 = 0.693 ± 0.014 and FL = 0.315 ± 0.011. The fraction F_{R} is calculated from the unitarity constraint to be F_{R} = −0.008 ± 0.007. These results are in agreement with the standard model predictions at next-to-next-to-leading order in perturbative quantum chromodynamics and represent an improvement in precision of 25 (29)% for F_{o} (F_{L}) with respect to the most precise single measurement. A limit on anomalous right-handed vector (VR), and left- and right-handed tensor (g_{L}, g_{R})tWb couplings is set while fixing all others to their standard model values. The allowed regions are [−0.11, 0.16] for V_{R}, [−0.08, 0.05] for g_{L}, and [−0.04, 0.02] for g_{R}, at 95% confidence level. Limits on the corresponding Wilson coefficients are also derived

Apoptosis in cancer: from pathogenesis to treatment

Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. It is also one of the most studied topics among cell biologists. An understanding of the underlying mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In some, the problem is due to too much apoptosis, such as in the case of degenerative diseases while in others, too little apoptosis is the culprit. Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not die. The mechanism of apoptosis is complex and involves many pathways. Defects can occur at any point along these pathways, leading to malignant transformation of the affected cells, tumour metastasis and resistance to anticancer drugs. Despite being the cause of problem, apoptosis plays an important role in the treatment of cancer as it is a popular target of many treatment strategies. The abundance of literature suggests that targeting apoptosis in cancer is feasible. However, many troubling questions arise with the use of new drugs or treatment strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely in human subjects

Wetlands for wastewater treatment and subsequent recycling of treated effluent : a review

Due to water scarcity challenges around the world, it is essential to think about non-conventional water resources to address the increased demand in clean freshwater. Environmental and public health problems may result from insufficient provision of sanitation and wastewater disposal facilities. Because of this, wastewater treatment and recycling methods will be vital to provide sufficient freshwater in the coming decades, since water resources are limited and more than 70% of water are consumed for irrigation purposes. Therefore, the application of treated wastewater for agricultural irrigation has much potential, especially when incorporating the reuse of nutrients like nitrogen and phosphorous, which are essential for plant production. Among the current treatment technologies applied in urban wastewater reuse for irrigation, wetlands were concluded to be the one of the most suitable ones in terms of pollutant removal and have advantages due to both low maintenance costs and required energy. Wetland behavior and efficiency concerning wastewater treatment is mainly linked to macrophyte composition, substrate, hydrology, surface loading rate, influent feeding mode, microorganism availability, and temperature. Constructed wetlands are very effective in removing organics and suspended solids, whereas the removal of nitrogen is relatively low, but could be improved by using a combination of various types of constructed wetlands meeting the irrigation reuse standards. The removal of phosphorus is usually low, unless special media with high sorption capacity are used. Pathogen removal from wetland effluent to meet irrigation reuse standards is a challenge unless supplementary lagoons or hybrid wetland systems are used

Emergence and phylodynamics of Citrus tristeza virus in Sicily, Italy

[EN] Citrus tristeza virus (CTV) outbreaks were detected in Sicily island, Italy for the first time in 2002. To gain insight into the evolutionary forces driving the emergence and phylogeography of these CTV populations, we determined and analyzed the nucleotide sequences of the p20 gene from 108 CTV isolates collected from 2002 to 2009. Bayesian phylogenetic analysis revealed that mild and severe CTV isolates belonging to five different clades (lineages) were introduced in Sicily in 2002. Phylogeographic analysis showed that four lineages co-circulated in the main citrus growing area located in Eastern Sicily. However, only one lineage (composed of mild isolates) spread to distant areas of Sicily and was detected after 2007. No correlation was found between genetic variation and citrus host, indicating that citrus cultivars did not exert differential selective pressures on the virus. The genetic variation of CTV was not structured according to geographical location or sampling time, likely due to the multiple introduction events and a complex migration pattern with intense co- and recirculation of different lineages in the same area. The phylogenetic structure, statistical tests of neutrality and comparison of synonymous and nonsynonymous substitution rates suggest that weak negative selection and genetic drift following a rapid expansion may be the main causes of the CTV variability observed today in Sicily. Nonetheless, three adjacent amino acids at the p20 N-terminal region were found to be under positive selection, likely resulting from adaptation events.A.W. and S.F.E. were supported by grant BFU2012-30805 from the Spanish Secretaria de Estado de Investigacion, Desarrollo e Innovacion and by a grant 22371 from the John Templeton Foundation. The opinions expressed in this publication are those of the authors and do not necessarily reflect the views of the John Templeton Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Davino, S.; Willemsen, A.; Panno. Stefano; Davino, M.; Catara, A.; Elena Fito, SF.; Rubio, L. (2013). Emergence and phylodynamics of Citrus tristeza virus in Sicily, Italy. PLoS ONE. 8:66700-66700. doi:10.1371/journal.pone.0066700S66700667008Domingo, E., & Holland, J. J. (1997). RNA VIRUS MUTATIONS AND FITNESS FOR SURVIVAL. Annual Review of Microbiology, 51(1), 151-178. doi:10.1146/annurev.micro.51.1.151Grenfell, B. T. (2004). Unifying the Epidemiological and Evolutionary Dynamics of Pathogens. Science, 303(5656), 327-332. doi:10.1126/science.1090727Moya, A., Holmes, E. C., & González-Candelas, F. (2004). The population genetics and evolutionary epidemiology of RNA viruses. Nature Reviews Microbiology, 2(4), 279-288. doi:10.1038/nrmicro863Gray, R. R., Tatem, A. J., Lamers, S., Hou, W., Laeyendecker, O., Serwadda, D., … Salemi, M. (2009). Spatial phylodynamics of HIV-1 epidemic emergence in east Africa. AIDS, 23(14), F9-F17. doi:10.1097/qad.0b013e32832faf61Holmes, E. C. (2008). Evolutionary History and Phylogeography of Human Viruses. Annual Review of Microbiology, 62(1), 307-328. doi:10.1146/annurev.micro.62.081307.162912Pybus, O. G., Suchard, M. A., Lemey, P., Bernardin, F. J., Rambaut, A., Crawford, F. W., … Delwart, E. L. (2012). Unifying the spatial epidemiology and molecular evolution of emerging epidemics. Proceedings of the National Academy of Sciences, 109(37), 15066-15071. doi:10.1073/pnas.1206598109Talbi, C., Lemey, P., Suchard, M. A., Abdelatif, E., Elharrak, M., Jalal, N., … Bourhy, H. (2010). Phylodynamics and Human-Mediated Dispersal of a Zoonotic Virus. PLoS Pathogens, 6(10), e1001166. doi:10.1371/journal.ppat.1001166Vijaykrishna, D., Bahl, J., Riley, S., Duan, L., Zhang, J. X., Chen, H., … Guan, Y. (2008). Evolutionary Dynamics and Emergence of Panzootic H5N1 Influenza Viruses. PLoS Pathogens, 4(9), e1000161. doi:10.1371/journal.ppat.1000161Gómez, P., Sempere, R. N., Aranda, M. A., & Elena, S. F. (2012). Phylodynamics of Pepino mosaic virus in Spain. European Journal of Plant Pathology, 134(3), 445-449. doi:10.1007/s10658-012-0019-0Lefeuvre, P., Martin, D. P., Harkins, G., Lemey, P., Gray, A. J. A., Meredith, S., … Heydarnejad, J. (2010). The Spread of Tomato Yellow Leaf Curl Virus from the Middle East to the World. PLoS Pathogens, 6(10), e1001164. doi:10.1371/journal.ppat.1001164TOMITAKA, Y., & OHSHIMA, K. (2006). A phylogeographical study of the Turnip mosaic virus population in East Asia reveals an ‘emergent’ lineage in Japan. Molecular Ecology, 15(14), 4437-4457. doi:10.1111/j.1365-294x.2006.03094.xWu, B., Blanchard-Letort, A., Liu, Y., Zhou, G., Wang, X., & Elena, S. F. (2011). Dynamics of Molecular Evolution and Phylogeography of Barley yellow dwarf virus-PAV. PLoS ONE, 6(2), e16896. doi:10.1371/journal.pone.0016896MORENO, P., AMBRÓS, S., ALBIACH-MARTÍ, M. R., GUERRI, J., & PEÑA, L. (2008). Citrus tristeza virus: a pathogen that changed the course of the citrus industry. Molecular Plant Pathology, 9(2), 251-268. doi:10.1111/j.1364-3703.2007.00455.xTatineni, S., Robertson, C. J., Garnsey, S. M., & Dawson, W. O. (2011). A plant virus evolved by acquiring multiple nonconserved genes to extend its host range. Proceedings of the National Academy of Sciences, 108(42), 17366-17371. doi:10.1073/pnas.1113227108Folimonova, S. Y. (2012). Superinfection Exclusion Is an Active Virus-Controlled Function That Requires a Specific Viral Protein. Journal of Virology, 86(10), 5554-5561. doi:10.1128/jvi.00310-12Bar-Joseph, M., Marcus, R., & Lee, R. F. (1989). The Continuous Challenge of Citrus Tristeza Virus Control. Annual Review of Phytopathology, 27(1), 291-316. doi:10.1146/annurev.py.27.090189.001451Davino, S., Rubio, L., & Davino, M. (2005). Molecular analysis suggests that recent Citrus tristeza virus outbreaks in Italy were originated by at least two independent introductions. European Journal of Plant Pathology, 111(3), 289-293. doi:10.1007/s10658-003-2815-zAlbiach-Marti, M. R., Mawassi, M., Gowda, S., Satyanarayana, T., Hilf, M. E., Shanker, S., … Dawson, W. O. (2000). Sequences of Citrus Tristeza Virus Separated in Time and Space Are Essentially Identical. Journal of Virology, 74(15), 6856-6865. doi:10.1128/jvi.74.15.6856-6865.2000Rubio, L., Ayllon, M. A., Kong, P., Fernandez, A., Polek, M., Guerri, J., … Falk, B. W. (2001). Genetic Variation of Citrus Tristeza Virus Isolates from California and Spain: Evidence for Mixed Infections and Recombination. Journal of Virology, 75(17), 8054-8062. doi:10.1128/jvi.75.17.8054-8062.2001Silva, G., Marques, N., & Nolasco, G. (2011). The evolutionary rate of citrus tristeza virus ranks among the rates of the slowest RNA viruses. Journal of General Virology, 93(2), 419-429. doi:10.1099/vir.0.036574-0Mawassi, M., Mietkiewska, E., Gofman, R., Yang, G., & Bar-Joseph, M. (1996). Unusual Sequence Relationships Between Two Isolates of Citrus Tristeza Virus. Journal of General Virology, 77(9), 2359-2364. doi:10.1099/0022-1317-77-9-2359Vives, M. C., Dawson, W. O., Flores, R., L√≥pez, C., Albiach-Mart√≠, M. R., Rubio, L., … Moreno, P. (1999). The complete genome sequence of the major component of a mild citrus tristeza virus isolate. Journal of General Virology, 80(3), 811-816. doi:10.1099/0022-1317-80-3-811Martín, S., Elena, S. F., Guerri, J., Moreno, P., Sambade, A., Rubio, L., … Vives, M. C. (2009). Contribution of recombination and selection to molecular evolution of Citrus tristeza virus. Journal of General Virology, 90(6), 1527-1538. doi:10.1099/vir.0.008193-0Vives, M. C., Rubio, L., Sambade, A., Mirkov, T. E., Moreno, P., & Guerri, J. (2005). Evidence of multiple recombination events between two RNA sequence variants within a Citrus tristeza virus isolate. Virology, 331(2), 232-237. doi:10.1016/j.virol.2004.10.037D’Urso, F., Sambade, A., Moya, A., Guerri, J., & Moreno, P. (2003). Variation of haplotype distributions of two genomic regions of Citrus tristeza virus populations from eastern Spain. Molecular Ecology, 12(2), 517-526. doi:10.1046/j.1365-294x.2000.01747.xSambade, A., Rubio, L., Garnsey, S. M., Costa, N., Muller, G. W., Peyrou, M., … Moreno, P. (2002). Comparison of viral RNA populations of pathogenically distinct isolates of Citrus tristeza virus : application to monitoring cross-protection. Plant Pathology, 51(3), 257-265. doi:10.1046/j.1365-3059.2002.00720.xReed, J. C., Kasschau, K. D., Prokhnevsky, A. I., Gopinath, K., Pogue, G. P., Carrington, J. C., & Dolja, V. V. (2003). Suppressor of RNA silencing encoded by Beet yellows virus. Virology, 306(2), 203-209. doi:10.1016/s0042-6822(02)00051-xFolimonova, S. Y., Robertson, C. J., Shilts, T., Folimonov, A. S., Hilf, M. E., Garnsey, S. M., & Dawson, W. O. (2009). Infection with Strains of Citrus Tristeza Virus Does Not Exclude Superinfection by Other Strains of the Virus. Journal of Virology, 84(3), 1314-1325. doi:10.1128/jvi.02075-09Kong, P., Rubio, L., Polek, M., & Falk, B. W. (2000). Virus Genes, 21(3), 139-145. doi:10.1023/a:1008198311398Powell, C. A., Pelosi, R. R., Rundell, P. A., & Cohen, M. (2003). Breakdown of Cross-Protection of Grapefruit from Decline-Inducing Isolates of Citrus tristeza virus Following Introduction of the Brown Citrus Aphid. Plant Disease, 87(9), 1116-1118. doi:10.1094/pdis.2003.87.9.1116Roistacher C, Dodds J. (1993) Failure of 100 mild Citrus tristeza virus isolates from california to cross protect against a challenge by severe sweet orange stem pitting isolates. Proc 12th Conf IOCV: 100–107.Ayllón, M. A., Rubio, L., Sentandreu, V., Moya, A., Guerri, J., & Moreno, P. (2006). Variations in Two Gene Sequences of Citrus Tristeza Virus after Host Passage. Virus Genes, 32(2), 119-128. doi:10.1007/s11262-005-6866-4Ayllón, M. A., Rubio, L., Moya, A., Guerri, J., & Moreno, P. (1999). The Haplotype Distribution of Two Genes of Citrus Tristeza Virus Is Altered after Host Change or Aphid Transmission. Virology, 255(1), 32-39. doi:10.1006/viro.1998.9566Sentandreu, V., Castro, J. A., Ayllón, M. A., Rubio, L., Guerri, J., González-Candelas, F., … Moya, A. (2005). Evolutionary analysis of genetic variation observed in citrus tristeza virus (CTV) after host passage. Archives of Virology, 151(5), 875-894. doi:10.1007/s00705-005-0683-xMatos, L. A., Hilf, M. E., Cayetano, X. A., Feliz, A. O., Harper, S. J., & Folimonova, S. Y. (2013). Dramatic Change in Citrus tristeza virus Populations in the Dominican Republic. Plant Disease, 97(3), 339-345. doi:10.1094/pdis-05-12-0421-reDavino, S., Davino, M., Sambade, A., Guardo, M., & Caruso, A. (2003). The First Citrus tristeza virus Outbreak Found in a Relevant Citrus Producing Area of Sicily, Italy. Plant Disease, 87(3), 314-314. doi:10.1094/pdis.2003.87.3.314aRUBIO, L., AYLLONl, M. A., GUERRI, J., PAPPU, H., NIBLETT, C., & MORENO, P. (1996). Differentiation of citrus tristeza closterovirus (CTV) isolates by single-strand conformation polymorphism analysis of the coat protein gene. Annals of Applied Biology, 129(3), 479-489. doi:10.1111/j.1744-7348.1996.tb05770.xLarkin, M. A., Blackshields, G., Brown, N. P., Chenna, R., McGettigan, P. A., McWilliam, H., … Higgins, D. G. (2007). Clustal W and Clustal X version 2.0. Bioinformatics, 23(21), 2947-2948. doi:10.1093/bioinformatics/btm404Tamura, K., Peterson, D., Peterson, N., Stecher, G., Nei, M., & Kumar, S. (2011). MEGA5: Molecular Evolutionary Genetics Analysis Using Maximum Likelihood, Evolutionary Distance, and Maximum Parsimony Methods. Molecular Biology and Evolution, 28(10), 2731-2739. doi:10.1093/molbev/msr121Kosakovsky Pond, S. L., Posada, D., Gravenor, M. B., Woelk, C. H., & Frost, S. D. W. (2006). GARD: a genetic algorithm for recombination detection. Bioinformatics, 22(24), 3096-3098. doi:10.1093/bioinformatics/btl474Martin, D. P., Lemey, P., Lott, M., Moulton, V., Posada, D., & Lefeuvre, P. (2010). RDP3: a flexible and fast computer program for analyzing recombination. Bioinformatics, 26(19), 2462-2463. doi:10.1093/bioinformatics/btq467Librado, P., & Rozas, J. (2009). DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics, 25(11), 1451-1452. doi:10.1093/bioinformatics/btp187Kimura M. (1985) The neutral theory of molecular evolution. Cambridge Univ Pr.Weir, B. S., & Cockerham, C. C. (1984). Estimating F-Statistics for the Analysis of Population Structure. Evolution, 38(6), 1358. doi:10.2307/2408641Pond, S. L. K., & Frost, S. D. W. (2005). Datamonkey: rapid detection of selective pressure on individual sites of codon alignments. Bioinformatics, 21(10), 2531-2533. doi:10.1093/bioinformatics/bti320Drummond, A. J., & Rambaut, A. (2007). BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evolutionary Biology, 7(1), 214. doi:10.1186/1471-2148-7-214Bielejec, F., Rambaut, A., Suchard, M. A., & Lemey, P. (2011). SPREAD: spatial phylogenetic reconstruction of evolutionary dynamics. Bioinformatics, 27(20), 2910-2912. doi:10.1093/bioinformatics/btr481Stamatakis, A. (2006). RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. Bioinformatics, 22(21), 2688-2690. doi:10.1093/bioinformatics/btl446Ott M, Zola J, Stamatakis A, Aluru S. (2007) Large-scale maximum likelihood-based phylogenetic analysis on the IBM BlueGene/L. Proceedings of the 19th ACM/IEEE conference on Supercomputing. Article No. 4.Shimodaira, H., & Hasegawa, M. (1999). Multiple Comparisons of Log-Likelihoods with Applications to Phylogenetic Inference. Molecular Biology and Evolution, 16(8), 1114-1116. doi:10.1093/oxfordjournals.molbev.a026201Soria-Carrasco, V., Talavera, G., Igea, J., & Castresana, J. (2007). The K tree score: quantification of differences in the relative branch length and topology of phylogenetic trees. Bioinformatics, 23(21), 2954-2956. doi:10.1093/bioinformatics/btm466Puigbo, P., Garcia-Vallve, S., & McInerney, J. O. (2007). TOPD/FMTS: a new software to compare phylogenetic trees. Bioinformatics, 23(12), 1556-1558. doi:10.1093/bioinformatics/btm13

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference