A quantitative test of the relationship between parasite dose and infection probability across different host-parasite combinations

Epidemiological models generally assume that the number of susceptible individuals that become infected within a unit of time depends on the density of the hosts and the concentration of parasites (i.e. mass-action principle). However, empirical studies have found significant deviations from this assumption due to biotic and abiotic factors, such as seasonality, the spatial structure of the host population and host heterogeneity with respect to immunity and susceptibility. In this paper, we examine the effect of the dose level of the bacterial endoparasite Pasteuria ramosa on the infection rate of its host, the water flea Daphnia magna. Using seven host clones and two parasite isolates, we measure the fraction of infected hosts after exposure to eight different parasite doses to determine whether there is variation in the infection process across different host clone-parasite isolate combinations. In five combinations, a pronounced dose-dependent infection pattern was found. Using a likelihood approach, we compare the infection data of these five combinations to the fit of three mathematical models: a mass-action model, a parasite antagonism model (i.e. an increase in the parasite dose leads to an under-proportionate increase in the infection rate per host) and a heterogeneous host model. We found that the host heterogeneity model, in which we assumed the existence of non-inherited phenotypic differences in host susceptibilities to the parasite, provides the best fit. Our analysis suggests that among 5 out of the 14 host clone-parasite isolate combinations that resulted in appreciable infections, non-genetic host heterogeneity plays an important role.     

Aluminum Inhibits Calpain-Mediated Proteolysis and Induces Human Neurofilament Proteins to Form ProteaseResistant High Molecular Weight Complexes

We studied the effects of aluminum salts on the degradation of human neurofilament subunits (NF-H, NF-M, and NF-L, the high, middle, and low molecular weight subunits, respectively) and other cytoskeletal proteins using calcium-activated neutral proteinase (calpain) purified from human brain. Calpain-mediated proteolysis of NF-L, tubulin, and glial fibrillary acidic protein (GFAP), three substrates that displayed constant digestion rates in vitro, was inhibited by AlCl3 (IC50 = 200 microM) and by aluminum lactate (IC50 = 400 microM). Aluminum salts inhibited proteolysis principally by affecting the substrates directly. After exposure to 400 microM aluminum lactate and removal of unbound aluminum, human cytoskeletal proteins were degraded two- to threefold more slowly by calpain. When cytoskeleton preparations were exposed to aluminum salt concentrations of 100 microM or higher, proportions of NF-M and NF-H formed urea-insoluble complexes of high apparent molecular mass, which were also resistant to proteolysis by calpain. Complexes of tubulin and of GFAP were not observed under the same conditions. Aluminum salts irreversibly inactivated calpain but only at high aluminum concentrations (IC50 = 1.2 and 2.1 mM for aluminum lactate and AlCl3, respectively), although longer exposure to the ion reduced by twofold the levels required for protease inhibition. These interactions of aluminum with neurofilament proteins and the effects on proteolysis suggest possible mechanisms for the impaired axoplasmic transport of neurofilaments and their accumulation in neuronal perikarya after aluminum administration in vivo.     

The inactivation of acetylcholinesterase by alpha-terthienyl and ultraviolet light Studies in vitro and in larvae of the mosquito Aedes aegypti

Acetylcholinesterase (EC 3.1.1.7) was inactivated photochemically in solution, in the presence of dissolved terthiophene sensitizers. Alpha-terthienyl (2,2′:5,2″-terthiophene) and its isomers 3,2′:5′,2″- and 3,2′:5′,3″-terthiophenes showed very similar sensitizing properties. With all three terthiophenes, the photosensitization was completely suppressed under anaerobic conditions, and therefore the inactivation process required the presence of oxygen. The enzyme was inactivated in vivo when fourth instar larvae of the mosquito Aedes aegypti were treated with alpha-terthienyl in the presence of long-wavelength ultraviolet light. No inactivation was observed when the organisms were treated with the ultraviolet light alone, with the chemical alone, or with a previously irradiated sample of the chemical. This paper represents the first example of acetylcholinesterase inactivation in vivo by a photoactive insecticide.     

The dystonia gene THAP1 controls DNA double-strand break repair choice

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Taking due care: moral obligations in dual use research

In the past decade, the perception of a bioterrorist threat has increased and created a demand on life scientists to consider the potential security implications of dual use research. This article examines a selection of proposed moral obligations for life scientists that have emerged to meet these concerns and the extent to which they can be considered reasonable. It also describes the underlying reasons for the concerns, how they are managed, and their implications for scientific values. Five criteria for what constitutes preventable harm are suggested and a number of proposed obligations for life scientists are considered against these criteria, namely, the obligations to prevent bioterrorism; to engage in response activities; to consider negative implications of research; not to publish or share sensitive information; to oversee and limit access to dangerous material; and to report activities of concern. Although bioterrorism might be perceived as an imminent threat, the analysis illustrates that this is beyond the responsibility of life scientists either to prevent or to respond to. Among the more reasonable obligations are duties to consider potential negative implications of one's research, protect access to sensitive material, technology and knowledge, and report activities of concern. Responsibility, therefore, includes obligations concerned with preventing foreseeable and highly probable harm. A central conclusion is that several of the proposed obligations are reasonable, although not unconditionally.     

Hodgkin Reed-Sternberg cells express 15-lipoxygenase-1 and are putative producers of eoxins in vivo: novel insight into the inflammatory features of classical Hodgkin lymphoma

Classical Hodgkin lymphoma has unique clinical and pathological features and tumour tissue is characterized by a minority of malignant Hodgkin Reed-Sternberg cells surrounded by inflammatory cells. In the present study, we report that the Hodgkin lymphoma-derived cell line L1236 has high expression of 15-lipoxygenase-1 and that these cells readily convert arachidonic acid to eoxin C(4), eoxin D(4) and eoxin E(4). These mediators were only recently discovered in human eosinophils and mast cells and found to be potent proinflammatory mediators. Western blot and immunocytochemistry analyses of L1236 cells demonstrated that 15-lipoxygenase-1 was present mainly in the cytosol and that the enzyme translocated to the membrane upon calcium challenge. By immunohistochemistry of Hodgkin lymphoma tumour tissue, 15-lipoxygenase-1 was found to be expressed in primary Hodgkin Reed-Sternberg cells in 17 of 20 (85%) investigated biopsies. The enzyme 15-lipoxygenase-1, however, was not expressed in any of 10 biopsies representing nine different subtypes of non-Hodgkin lymphoma. In essence, the expression of 15-lipoxygenase-1 and the putative formation of eoxins by Hodgkin Reed-Sternberg cells in vivo are likely to contribute to the inflammatory features of Hodgkin lymphoma. These findings may have important diagnostic and therapeutic implications in Hodgkin lymphoma. Furthermore, the discovery of the high 15-lipoxygenase-1 activity in L1236 cells demonstrates that this cell line comprises a useful model system to study the chemical and biological roles of 15-lipoxygenase-1.     

Calpain-mediated proteolysis of microtubule associated proteins MAP1B and MAP2 in developing brain

Microtubule associated proteins MAP1B and MAP2 are important components of the neuronal cytoskeleton. During early development of the brain, MAP1B (340 kDa) is present as two isoforms that differ in their level of phosphorylation, while MAP2 is expressed as a single high molecular weight isoform (MAP2B, 280 kDa) and a low molecular weight form (MAP2C, 70 kDa). In this study we examined and compared the sensitivities of MAP1B and MAP2, obtained from MT preparations and brain homogenates of young rats, to degradation by calcium-activated neutral protease, calpain II. We found that in MAPs prepared from microtubules the two isoforms of MAP1B had comparable sensitivity to calpain-mediated proteolysis. Similarly, the high and low molecular weight forms of MAP2 were equally sensitive to digestion by calpain. However, although both MAPs were very susceptible to calpain-mediated proteolysis, MAP1B was more resistant to degradation by calpain than MAP2. Furthermore, the endogenous degradation of MAPs in neonate brain homogenates was calcium-dependent and inhibited by leupeptin, and the pattern of degradation products for MAP1B and MAP2 was similar to that of calpain-mediated proteolysis. These data suggest that calpain can play a role in the regulation of MAPs levels during brain development, in relation to normal neuronal differentiation and disorders associated with neurodegeneration.