The sievert: an enigmatic unit.

The concept of effective dose with its unit, the sievert, is frequently misunderstood. Originally conceived to simplify radiation protection management, this concept is also proposed for another and very ambitions objective: a quantitative evaluation of the risks of radio-induced diseases, whatever the dose, the dose rate, the nature of radiation.... However, using the sievert for the prediction of risks of cancer or hereditary diseases is hazardous, and errors of prediction have been observed these last decades, for example the lack of prediction of the number of thyroid cancer in the very young children after the Chernobyl accident, and the overestimation of the risks such as leukaemia, other cancer and hereditary diseases. What are one sievert and its subunits?     

The antiparasitic actions of plant jasmonates

Jasmonates are a group of small lipids produced in plants, which function as plant stress hormones. We have previously shown that jasmonates can exert significant cytotoxic effects upon human cancer cells. The purpose of the present study was to determine the effects of jasmonates on parasites. To that end, we chose 2 major human blood parasites, Plasmodium falciparum, a unicellular parasite, and Schistosoma mansoni, a multicellular helminth parasite, and studied the effects of jasmonates on these parasites in vitro. We found that jasmonates are cytotoxic toward both parasites, with P. falciparum being the more susceptible. Jasmonates did not cause any damage to control human erythrocytes at the maximum concentration used in the experiments. This is the first study demonstrating the antiparasitic potential of plant-derived jasmonates.     

Ecology's dark matter: The elusive and enigmatic niche

Ecologists are often frustrated that their universe, populated by strange and wilful creatures, seems fuzzy and unpredictable. Physicists, in contrast, seem to have it much better. But that's because we usually focus on Newtonian physics. In fact, physicists seem happy to live with all kinds of strange beasts, including dark matter, something they have never seen, but which they nevertheless believe makes up most of the matter in the universe. Here I argue that niches are ecology's dark matter. We are embarrassed by them, because we do not quite know what they are, and yet their presence can be universally felt; otherwise, ecological communities, like galaxies without dark matter, would simply collapse. I describe how we could potentially better describe these dark shapes that haunt our science and why this is important. In particular, I present the outline of a method for demonstrating whether or not plant species have complementary resource-use niches; something that has been difficult to show unequivocally. The presence of such resource-use niches would put to rest once and for all the notion of species equivalence and the neutral world that this assumption entails. I conclude that ecologists should take a leaf out of the physicists’ book and accept that the continued search for the esoteric niche is a legitimate and central (if frustrating) part of ecology.     

The Type IVB secretion system: an enigmatic chimera

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The challenges of developing novel antiparasitic drugs

Only a few novel classes of antiparasitic drugs have emerged over the last few decades, reflecting the difficulties associated with bringing a safe, effective molecule to market. In recent years, the screening paradigm has shifted from empirical whole parasite screening towards mechanism-based high throughput screening. This approach requires investment in molecular parasitology and in understanding the basic biology of parasites, as well as requiring considerable investment in an infrastructure for screening. Add to this the fact that the drug discovery process is iterative with high attrition, the Animal Health industry by necessity must focus on discovering medicines for diseases, which will deliver a return on investment. In recent years the rapid progression of genomics has unlocked a plethora of tools for target identification, validation and screening, revolutionising mechanism-based screening for antiparasitic drug discovery. The challenge still remains; however, to identify novel chemical entities with the properties required to deliver a safe, effective antiparasitic drug.     

Praziquantel: an urgent and exciting challenge

The anthelmintic drug praziquantel has proved useful in the treatment of schistosomiasis. The precise mechanism by which praziquantel kills the parasites has yet to be elucidated. Here, John Kusel and colleagues review the current theories on praziquantel action and suggest future avenues for research, which becomes urgent in the light of some reports of drug resistance.     

The enigmatic oxygen-avid hemoglobin of Ascaris

The parasitic nematode Ascaris lives in the low-oxygen intestinal folds of over one billion people world-wwide. The worm has an octameric hemoglobin that binds oxygen four orders of magnitude more tightly than does human hemogobin. Our studies have focused on elucidating the molecular mechanism of oxygen avidity, the basis of multimerization and the function of this remarkable molecule. We now believe that we understand a fair amount about the molecular interactions that result in enhanced avidity, have some preliminary ideas on octamer formation, and have some hypotheses about possible function. Along the way we have stumbled into the disciplines of intron evolution, sterol biosynthesis and oxygen-regulated gene expression.     

PCSK9: an enigmatic protease

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol metabolism by controlling the levels of low density lipoprotein (LDL) particles that circulate in the bloodstream. Several gain-of-function and loss-of-function mutations in the PCSK9 gene, that occur naturally, have been identified and linked to hypercholesterolemia and hypocholesterolemia, respectively. PCSK9 expression has been shown to be regulated by sterol regulatory element binding proteins (SREBPs) and statins similar to other genes involved in cholesterol homeostasis. The most critical finding concerning PCSK9 is that this protease is able to influence the number of LDL receptor molecules expressed on the cell surface. Studies have demonstrated that PCSK9 acts mainly by enhancing degradation of LDL receptor protein in the liver. Inactivation of PCSK9 in mice reduces plasma cholesterol levels primarily by increasing hepatic expression of LDL receptor protein and thereby accelerating clearance of circulating LDL cholesterol. The objective of this review is to summarize the current information related to the regulation and function of PCSK9 and to identify gaps in our present knowledge.     

The enigmatic reaction of flavins with oxygen

The reaction of flavoenzymes with oxygen remains a fascinating area of research because of its relevance for reactive oxygen species (ROS) generation. Several exciting recent studies provide consistent mechanistic clues about the specific functional and structural properties of the oxidase and monooxygenase flavoenzymatic systems. Specifically, the spatial arrangement of the reacting oxygen that is in direct contact with the flavin group is emerging as a crucial factor that differentiates between oxidase and monooxygenase enzymes. A challenge for the future will be to use these emerging concepts to rationally engineer flavoenzymes, paving the way to new research avenues with far-reaching implications for oxidative biocatalysis and metabolic engineering.     

The enigmatic megakaryocyte gradually reveals its secrets

The recent cloning of thrombopoietin has brought many insights into the cellular and molecular mechanisms of megakaryocyte and platelet development. Thrombopoietin was cloned based on its binding to the product of the proto-oncogene c-mpl and was found to affect all aspects of thrombopoiesis. Many of the molecular pathways that mediate thrombopoietin action have been discerned. Upon hormone binding, the megakaryocyte thrombopoietin receptor homodimerizes, activating members of the JAK family of kinases, which, in turn, phosphorylate the receptor, generating docking sites for second messengers that affect multiple signalling pathways. Ultimately, cellular proliferative and anti-apoptotic mechanisms are initiated, increasing megakaryocyte numbers, as are processes that uncouple DNA synthesis from nuclear and cytoplasmic division, generating polyploid cells. As the net result of thrombopoietin action is an expansion of cells that give rise to mature platelets, the availability of the recombinant hormone has provided new opportunities to manipulate blood cell development for therapeutic benefit. BioEssays 21:353–360, 1999. © 1999 John Wiley & Sons, Inc.     

Nitric oxide: an antiparasitic molecule of invertebrates

Since Furchgott, Ignarro and Murad won the Nobel prize in 1998 for their work on the role of nitric oxide (NO) as a signaling molecule, many reports have shown the seemingly limitless range of body functions controlled by this compound. In vertebrates, the role of NO as a defense against infection caused by viruses, bacteria, and protozoan and metazoan parasites has been known for several years. New evidence, however, shows that NO is also important in defending invertebrates against parasites. This discovery is a breakthrough in the understanding of how the invertebrate immune system works, and it has implications for the emerging field of invertebrate ecological immunology.