The role of host PrP in Transmissible Spongiform Encephalopathies

PrP has a central role in the Transmissible Spongiform Encephalopathies (TSEs), and mutations and polymorphisms in host PrP can profoundly alter the host's susceptibility to a TSE agent. However, precisely how host PrP influences the outcome of disease has not been established. To investigate this we have produced by gene targeting a series of inbred lines of transgenic mice expressing different PrP genes. This allows us to study directly the influence of the host PrP gene in TSEs. We have examined the role of glycosylation, point mutations, polymorphisms and PrP from different species on host susceptibility and the disease process both within the murine species and across species barriers.     

The role of plasma noradrenaline in health and disease

This paper proposes that plasma noradrenaline plays a central role in the physiology and pathophysiology of the macrocirculation, the heart, veins and arteries. The proposal stems, in the final analysis, from the finding that noradrenaline dilates the canine lateral saphenous vein when it is released from its microcirculation, the vasa venarum. The concentration threshold of the effect is estimated to be at least eight times lower than the threshold of the constrictor effect of intralumenal noradrenaline. Combined with other evidence, the finding indicates that, contrary to opinion, plasma noradrenaline has an effective β₁-agonist hormonal effect on the macrocirculation, at normal concentrations. It also indicates that noradrenaline has a bi-polar effect. The reason it has that effect is that noradrenaline is a primary biological stimulus and like all primary stimuli investigated to date, it can be expected to have two cross-inhibitory components, commonly referred to as excitor and lateral inhibitory. When examined, neuronal noradrenaline shows the features characteristic of excitor components in general and plasma noradrenaline shows those characteristic of inhibitory components. The most significant of the latter is that inhibitory components are the most potent physiological modulators of excitor components. A striking example of that modulation effect occurs in smooth muscle contraction where muscles contracted by neuronal noradrenaline stimulation appear to be incapable of relaxing without stimulation by plasma noradrenaline-hence the proposition that vascular stenosis and cardiospasm are caused by a pathological loss of plasma noradrenaline stimulation. By triggering turbulence, cholesterol plaques increase the arterial microcirculatory flow and so increase the β₁-agonist effect of plasma noradrenaline. This paper proposes that this cholesterol driven increase in the microcirculatory effect of plasma noradrenaline is the cause of the arteriosclerotic syndrome, a proposition that is consistent with the success of beta-blockade in treating manifestations of the syndrome. The paper concludes by examining a variety of conditions, including dissecting aneurysms, dilator cardiac failure, angina, myocardial infarction, hypertension, eclampsia and cirrhosis and pointing out that all of them, like varicose veins, show evidence consistent with having been caused by a turbulence induced increase in a β₁-agonist stimulatory effect of microcirculatory plasma noradrenaline.     

The role of endogenous bromotyrosine in health and disease

Abstract

Bromotyrosine is a stable by-product of eosinophil peroxidase activity, a result of eosinophil activation during an inflammatory immune response. The elevated presence of bromotyrosine in tissue, blood, and urine in medical conditions involving eosinophil activation has highlighted the potential role of bromotyrosine as a medical biomarker. This is highly beneficial in a paediatric setting as a urinary noninvasive biomarker. However, bromotyrosine and its derivatives may exert biological effects, such as protective effects in the brain and pathogenic effects in the thyroid. Understanding these pathways may yield therapeutic advancements in medicine. In this review, we summarize the existing evidence present in literature relating to bromotyrosine formation and metabolism, identify the biological actions of bromotyrosine and evaluate the feasibility of bromotyrosine as a medical biomarker.     

The role of PNPLA3 in health and disease

The human patatin-like phospholipase domain-containing 3 (PNPLA3) gene encodes for a protein of 481 amino-acids. The variant rs738409 is a cytosine to guanine substitution, encoding for the isoleucine to methionine substitution at position 148 (I148M) of the protein. This variant is strongly associated with the entire spectrum of liver disease. Although this variant is one of the best characterized and deeply studied, the mechanism behind the PNPLA3 and the liver disease is still not well defined. Functionally, it has become clear that the PNPLA3 protein is an enzyme with lipase activity towards triglycerides and retinyl esters, and acyltransferase activity on phospholipids.The aim of this review is to collect the latest data, obtained by in vitro and in vivo experiments, on the functional aspects of the PNPLA3 protein.Defining the precise role of PNPLA3 in the liver lipid metabolism, in order to develop novel therapies for the treatment of liver disease, will be the key of future research.     

The cellular prion protein (PrP(C)): its physiological function and role in disease

Prion diseases are caused by conversion of a normal cell-surface glycoprotein (PrP(C)) into a conformationally altered isoform (PrP(Sc)) that is infectious in the absence of nucleic acid. Although a great deal has been learned about PrP(Sc) and its role in prion propagation, much less is known about the physiological function of PrP(C). In this review, we will summarize some of the major proposed functions for PrP(C), including protection against apoptotic and oxidative stress, cellular uptake or binding of copper ions, transmembrane signaling, formation and maintenance of synapses, and adhesion to the extracellular matrix. We will also outline how loss or subversion of the cytoprotective or neuronal survival activities of PrP(C) might contribute to the pathogenesis of prion diseases, and how similar mechanisms are probably operative in other neurodegenerative disorders.     

The role of microorganisms in coral health, disease and evolution

Coral microbiology is an emerging field, driven largely by a desire to understand, and ultimately prevent, the worldwide destruction of coral reefs. The mucus layer, skeleton and tissues of healthy corals all contain large populations of eukaryotic algae, bacteria and archaea. These microorganisms confer benefits to their host by various mechanisms, including photosynthesis, nitrogen fixation, the provision of nutrients and infection prevention. Conversely, in conditions of environmental stress, certain microorganisms cause coral bleaching and other diseases. Recent research indicates that corals can develop resistance to specific pathogens and adapt to higher environmental temperatures. To explain these findings the coral probiotic hypothesis proposes the occurrence of a dynamic relationship between symbiotic microorganisms and corals that selects for the coral holobiont that is best suited for the prevailing environmental conditions. Generalization of the coral probiotic hypothesis has led us to propose the hologenome theory of evolution.     

The role of the local microbial ecosystem in respiratory health and disease

Respiratory tract infections are a major global health concern, accounting for high morbidity and mortality, especially in young children and elderly individuals. Traditionally, highly common bacterial respiratory tract infections, including otitis media and pneumonia, were thought to be caused by a limited number of pathogens including Streptococcus pneumoniae and Haemophilus influenzae. However, these pathogens are also frequently observed commensal residents of the upper respiratory tract (URT) and form—together with harmless commensal bacteria, viruses and fungi—intricate ecological networks, collectively known as the ‘microbiome’. Analogous to the gut microbiome, the respiratory microbiome at equilibrium is thought to be beneficial to the host by priming the immune system and providing colonization resistance, while an imbalanced ecosystem might predispose to bacterial overgrowth and development of respiratory infections. We postulate that specific ecological perturbations of the bacterial communities in the URT can occur in response to various lifestyle or environmental effectors, leading to diminished colonization resistance, loss of containment of newly acquired or resident pathogens, preluding bacterial overgrowth, ultimately resulting in local or systemic bacterial infections. Here, we review the current body of literature regarding niche-specific upper respiratory microbiota profiles within human hosts and the changes occurring within these profiles that are associated with respiratory infections.     

The multifaceted role of lemur tyrosine kinase 3 in health and disease

In the last decade, LMTK3 (lemur tyrosine kinase 3) has emerged as an important player in breast cancer, contributing to the advancement of disease and the acquisition of resistance to therapy through a strikingly complex set of mechanisms. Although the knowledge of its physiological function is largely limited to receptor trafficking in neurons, there is mounting evidence that LMTK3 promotes oncogenesis in a wide variety of cancers. Recent studies have broadened our understanding of LMTK3 and demonstrated its importance in numerous signalling pathways, culminating in the identification of a potent and selective LMTK3 inhibitor. Here, we review the roles of LMTK3 in health and disease and discuss how this research may be used to develop novel therapeutics to advance cancer treatment.     

The role of PP5 and PP2C in cardiac health and disease

Protein phosphatases are important, for example, as functional antagonists of β-adrenergic stimulation of the mammalian heart. While β-adrenergic stimulations increase the phosphorylation state of regulatory proteins and therefore force of contraction in the heart, these phosphorylations are reversed and thus force is reduced by the activity of protein phosphatases. In this context the role of PP5 and PP2C is starting to unravel. They do not belong to the same family of phosphatases with regard to sequence homology, many similarities with regard to location, activation by lipids and putative substrates have been worked out over the years. We also suggest which pathways for regulation of PP5 and/or PP2C described in other tissues and not yet in the heart might be useful to look for in cardiac tissue. Both phosphatases might play a role in signal transduction of sarcolemmal receptors in the heart. Expression of PP5 and PP2C can be increased by extracellular stimuli in the heart. Because PP5 is overexpressed in failing animal and human hearts, and because overexpression of PP5 or PP2C leads to cardiac hypertrophy and KO of PP5 leads to cardiac hypotrophy, one might argue for a role of PP5 and PP2C in heart failure. Because PP5 and PP2C can reduce, at least in vitro, the phosphorylation state of proteins thought to be relevant for cardiac arrhythmias, a role of these phosphatases for cardiac arrhythmias is also probable. Thus, PP5 and PP2C might be druggable targets to treat important cardiac diseases like heart failure, cardiac hypertrophy and cardiac arrhythmias.     

The GPI-anchoring of PrP

The cellular prion protein (PrP^C) is an N-glycosylated GPI-anchored protein usually present in lipid rafts with numerous putative functions. When it changes its conformation to a pathological isoform (then referred to as PrP^Sc), it is an essential part of the prion, the agent causing fatal and transmissible neurodegenerative prion diseases. There is growing evidence that toxicity and neuronal damage on the one hand and propagation/infectivity on the other hand are two distinct processes of the disease and that the GPI-anchor attachment of PrP^C and PrP^Sc plays an important role in protein localization and in neurotoxicity. Here we review how the signal sequence of the GPI-anchor matters in PrP^C localization, how an altered cellular localization of PrP^C or differences in GPI-anchor composition can affect prion infection, and we discuss through which mechanisms changes on the anchorage of PrP^C can modify the disease process.     

The potential role of sialoadhesin as a macrophage recognition molecule in health and disease

Sialoadhesin is a macrophage-restricted transmembrane glycoprotein of 185 kDa that mediates cell–cell interactions through recognition of Neu5Acα2,3Gal in glycoconjugates. The extracellular region of sialoadhesin is composed of seventeen immunoglobulin-like domains, of which the amino-terminal two are highly-related structurally and functionally to the amino-terminal domains of CD22, myelin associated glycoprotein and CD33. These proteins, collectively known as the sialoadhesin family, are able to mediate sialic acid-dependent binding with distinct specificities for both the type of sialic acid and its linkage to subterminal sugars. In this review we discuss our recent studies on sialoadhesin and suggest how this molecule may contribute to a range of macrophage functions, both under normal conditions as well as during inflammatory reactions. Abbreviations: Ig, immunoglobulin; CEA, carcinoembryonic antigen; MAG, myelin associated glycoprotein; SMP Schwann cell myelin protein; mAb, monoclonal antibody; Chinese hamster ovary (CHO); UTR, untranslated region This revised version was published online in November 2006 with corrections to the Cover Date.     

Platelet-derived growth factor and its role in health and disease

Platelet-derived growth factor (PDGF) was first discovered in platelets because they are the principal source of mitogenic activity in whole blood serum for mesenchymal cells in culture. PDGF is ubiquitous in that it can be formed by a large number of normal cells as well as many varieties of transformed cells. However, its expression and biological activity appear to be controlled at a number of different levels. The molecule consists of two peptide chains (termed 'A' and 'B') and is found as one of at least three possible isoforms, (AB, AA or BB). Each of these isoforms binds to a high-affinity cell-surface receptor that is composed of two different subunits, each of which has specificity for one or the other of the peptide chains of PDGF. The two receptor subunits are present in differing amounts on different cell types, and therefore the capacity of the different isoforms of PDGF to induce mitogenesis depends on the specific PDGF isoform and the relative numbers of receptor subunits present on the responding cell. In addition to inducing cell replication, PDGF elicits a number of intracellular signals related to mitogenesis, is chemotactic, is a vasoconstrictor, activates leukocytes, and modulates extracellular matrix turnover. This growth factor is probably involved in a number of biologically important events including wound repair, embryogenesis and development, and inflammation, leading to fibrosis, atherosclerosis and neoplasia.     

BrainModes: the role of neuronal oscillations in health and disease

The core idea of complexity science--namely how macroscopic phenomena emerge from the interactions between microscopic quantities--is particularly relevant to the study of the human brain. It is in this context that the term "BrainModes" was adopted to explore how cooperative phenomena (or 'modes' of activity) occurring at one spatial or temporal scale give rise to coherent structures at other scales. This Special Issue reports the 2009 BrainModes Workshop, held in Bristol (December 2009) which focussed on the fusion of theoretical, computational, experimental and clinical methods for enhancing our understanding of the role played by neuronal oscillations in healthy and diseased brain states.     

Gut flora in health and disease: potential role of probiotics

In a young evolving science, there are always more questions than answers. That is also the situation in the emerging field of Probiotics, and this was made very clear at the International Probiotics Workshop in Amsterdam. In the report of this workshop, we present a selection of the most urgent questions in the field of probiotics. In addition, we propose a few strategies for the future of probiotics research. During the workshop, 120 experts--from disciplines including Human Nutrition, Gastroenterology, Nutritional Therapy, Cell Biology, Microbiology and Immunology--discussed new views on microbe-host interactions and the role of probiotics in prevention and alleviation of gastro-intestinal, atopic and auto-immune diseases. There is a general consensus among the experts that administering defined strains can help in preventing and curing gut flora related diseases: the first clinical trials show a promising role for probiotics. But the system is very complex, and most underlying mechanisms are still unclear. Rapid progress in this field will depend largely on the collaboration between fundamental researchers from different disciplines and medical specialists. Besides, more clinical studies are required to convince authorities and the public of the value of microbial therapies.     

The role of inositol 1,4,5-trisphosphate receptors in the regulation of bile secretion in health and disease

Ca2+ signaling via the inositol 1,4,5-trisphosphate receptor (InsP3R) is a ubiquitous mechanism for regulation of cell function, yet very little is known about the role of the InsP3R in specific disease states. Converging lines of evidence suggest that the liver may provide a model for the role of the InsP3R in health and disease. Ca2+ signaling is mediated entirely by the InsP3R in hepatocytes and cholangiocytes, the two types of epithelia in the liver. Here we review the role of specific InsP3R isoforms and the physiological effects of InsP3R-mediated Ca2+ signals in both of these types of epithelia. In addition, we review evidence that the InsP3R is lost from cholangiocytes in cholestatic forms of liver disease, and discuss this as a possible final common pathway for cholestasis.