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 …

I and i

http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.

/pdf/metagenomic-biomarker-discovery-and-explanation-x530ilzkca.pdf

Metagenomic biomarker discovery and explanation

We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.

http://science.sciencemag.org/content/sci/298/5600/1912.full.pdf

The Protein Kinase Complement of the Human Genome

An expert panel was convened in October 2013 by the International Scientific Association for Probiotics and Prebiotics (ISAPP) to discuss the field of probiotics. It is now 13 years since the definition of probiotics and 12 years after guidelines were published for regulators, scientists and industry by the Food and Agriculture Organization of the United Nations and the WHO (FAO/WHO). The FAO/WHO definition of a probiotic--"live microorganisms which when administered in adequate amounts confer a health benefit on the host"--was reinforced as relevant and sufficiently accommodating for current and anticipated applications. However, inconsistencies between the FAO/WHO Expert Consultation Report and the FAO/WHO Guidelines were clarified to take into account advances in science and applications. A more precise use of the term 'probiotic' will be useful to guide clinicians and consumers in differentiating the diverse products on the market. This document represents the conclusions of the ISAPP consensus meeting on the appropriate use and scope of the term probiotic.

/pdf/expert-consensus-document-the-international-scientific-1zd5d1fmxy.pdf

Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic

Thirty years of research on the role of immune-mediated cytotoxic activity in the tissue injury of inflammatory bowel disease (IBD) has yielded only inconclusive data on the relevance of cytotoxic mechanisms. Two hypotheses have been advanced. One is that the destruction of target cells is mediated by direct recognition of target antigens by cytotoxic cells which in turn triggers lysis. Another hypothesis is that lysis occurs via an indirect bystander mechanism in which cells do not recognize a specific antigen on the target, but upon nonspecific activation release cytokines which are capable of lysing the target. The authors have investigated both hypotheses and studied the role of cytotoxic T cells and cytotoxic rectors released from activated T cells in the destruction of epithelial cells. Elevated levels of cytotoxic T cells were found in peripheral blood lymphocytes of patients with IBD, particularly Crohn's disease. The cytotoxic T cells were contained within the Leu 7

/pdf/immune-mediated-cytotoxicity-in-inflammatory-bowel-disease-3exdv3xney.pdf

Immune-Mediated Cytotoxicity in Inflammatory Bowel Disease

Gastrointestinal (GI) disease is a common manifestation of HTV infection. Symptoms may result from the acquisition of intestinal infection, but in certain cases functional and mucosal abnormality may

Mucosal Substance P Receptor Expression in HIV Infection and Inflammatory Bowel Disease

Dysplasia surveillance by microscopic examination of endoscopic biopsy sections from patients with ulcerative colitis is a subjective and insensitive method of identifying those at particular risk of developing cancer. The need for better molecular and cytochemical markers of cancer risk is well recognized. The search for such markers has included examination of mucin and other glycoprotein expression, flow cytometric profile of DNA content, and molecular analysis of oncogene mutations and tumor suppressor genes. Although promising, these approaches have not yet yielded a validated, reliable cancer marker of high predictive value. Light microscopy is still the most practical and conveniently available approach. Debate, therefore, focuses on the effectiveness of the current practice and whether it can be improved.

Discontent with dysplasia surveillance in ulcerative colitis

/pdf/is-the-mucosal-route-of-administration-essential-for-2iqulilbyx.pdf

Is the Mucosal Route of Administration Essential for Probiotic Function? Subcutaneous Administration is Associated with Attenuation of Murine Colitis and Arthritis

There is compelling evidence to show that the development and functioning of the mucosal immune response is dependent on microbial exposure early in post-natal life. This is accomplished by bacterial colonisation of the gut and exposure to childhood mucosal infections. Without this stimulation, development of the gut-associated lymphoid tissue is rudimentary and generation of immune responses is suboptimal. The mucosal immune response is the sense of danger within the microbial environment. As with other senses, it has receptors, an afferent and efferent limb and central integration, and it exhibits memory and learning. Also in common with other senses, it requires appropriate input and conditioning for optimal behaviour. Misbehaviour or misperception of the microenvironment is a risk factor for immune dysfunction and inflammatory bowel disease (IBD). The study of germ-free and flora-defined animals using modern molecular techniques and laser microdissection is beginning to facilitate the identification of the signals and transduction pathways involved in mediating the regulatory influences of the flora on the mucosal immune function. Probiotics may be operationally defined as commensal bacteria, which may be exploited as food-grade organisms for health benefit. It seems likely that probiotics use the same signalling pathways for engagement of the immune response as those used by commensals resident within the gut. In addition, it is clear that manipulation of the gut flora with probiotics, prebiotics and synbiotics offers a means for studying hostflora interactions. It also provides a relatively untapped strategy for treating mucosal inflammatory disorders. Commensal bacteria within the gut vary in their capacity to drive the inflammatory process. Because lactobacilli, bifidobacteria and other bacterial species have no apparent proinflammatory activity, they have been explored for probiotic potential. Despite exaggerated and unsupported claims for efficacy by some commercial sources, there is emerging evidence supporting a role for probiotic and prebiotic strategies in inflammatory bowel disease and non-IBD conditions such as atopy and infection. That probiotics exert an immunomodulatory influence has been well demonstrated in flora-defined animals and in gene-expression studies of epithelial and dendritic cells co-cultured with different probiotic strains. In vivo, there is evidence of engagement with the immune system from controlled studies of immune reactivity against consumed probiotics in humans. In addition, the impact of probiotic consumption on systemic and mucosal cytokines has been demonstrated with several probiotic strains in murine trials. Reduced intestinal and peripheral production of tumor necrosis factor (TNF), interferon, and interleukin (IL)-12 in association with maintained or enhanced levels of transforming growth factor (TGF)are evident. This suggests that probiotics may exert their immunomodulatory effects at the level of regulatory T cells rather than at the level of polarised Th1 or Th2 effector cells. Probiotic engagement with the immune system probably occurs first with intestinal dendritic cells. Modulation of dendritic cell function with lactobacilli has been examined, and remarkable plasticity of dendritic cell responses to different organisms has been shown. More importantly, while responses to invasive pathogens tend to be similar, irrespective of the source of dendritic and other lymphoid cells, the response to probiotic organisms demonstrates regional specialisation. This is of importance for the investigation of host-probiotic interactions, and studies based on peripheral blood should be interpreted with caution, as results cannot be extrapolated loosely to the mucosal immune response. However, the optimum combination of probiotic organisms for immunomodulation has not been defined, and indeed, the possibility that some combinations might be antagonistic rather than synergistic has not been determined. Another strategy that is being explored is rigorous definition of microbial, immunologic and functional characteristics of individual probiotic strains so that mechanisms can be clarified and then appropriate combinations designed if necessary. Furthermore, probiotic performance should be defined in terms of the health benefit that is required (e.g., anti-inflammatory or antiinfective or both). Furthermore, in complex disorders such as IBD, there may be subset-specific indications requiring strain-specific prescriptions. There are several additional factors that may confound the use of probiotics for immune-mediated disorders Address correspondence and reprint requests to: Prof. Fergus Shanahan, Alimentary Pharmabiotic Centre, University College Cork, Ireland; Fax: 353-21-4345300; (e-mail: fshanahan@ucc.ie). Journal of Pediatric Gastroenterology and Nutrition 39:S748–S749 © June 2004 Lippincott Williams & Wilkins, Philadelphia

Fergus Shanahan

Papers

Immune-Mediated Cytotoxicity in Inflammatory Bowel Disease

Mucosal Substance P Receptor Expression in HIV Infection and Inflammatory Bowel Disease

Discontent with dysplasia surveillance in ulcerative colitis

Is the Mucosal Route of Administration Essential for Probiotic Function? Subcutaneous Administration is Associated with Attenuation of Murine Colitis and Arthritis

Probiotics and the immune response: how much can we expect?