II Letter to the editor in response to J. Suhnel's comment on the paper: A three-dimensional model to analyze drug-drug interactions : Prichard, M.N. and Shipman, C., Jr. (1990) Antiviral Res. 14, 181-206

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30292/1/0000694.pd

I Letter to the editor in response to the paper: Efficacy of ganciclovir in combination with zidovudine against cytomegalovirus in vitro and in vivo : Freitas, V.R., Fraser-Smith, E.B., Chiu, S., Michelson, S. and Schatzman, R.C. (1993) Antiviral Res. 21, 301-315

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31414/1/0000331.pd

Oceanic inside corner detachments of the Limassol Forest area, Troodos ophiolite, Cyprus

Flat-lying extensional detachment faults have been imaged in the inside corner regions of ridge-transform intersections on the Mid-Atlantic Ridge. Exposed detachment surfaces are 10 km or more across, and are corrugated in the direction of spreading, as are continental detachments. Beneath the detachments lie core complexes of peridotite and gabbro; these are overlain by blocks of crustal material. We argue here that similar detachments are an essential component of the Limassol Forest area of the Troodos ophiolite in Cyprus, which lies south of the Arakapas Fault zone, previously recognized as a palaco-transform fault, and here interpreted as a transform fault that evolved into a fracture zone. In the Limassol Forest, core complexes of mantle peridotite can be shown to have been exposed at the sea floor, or to have been covered by overlapping crustal blocks, separated from the peridotite core and from each other by low-angle extensional faults. The extension can be shown to have occured shortly after crustal construction, and the already extended terrain was then intruded by swarms of dykes and plutons. We interpret these relations as arising when crust is constructed in an inside corner area, extended by detachment faulting, deformed further during slip along the transform, and then intruded by new magma as it passes the second spreading centre. The structurally deeper parts of the crustal blocks that overlie the detachment lie broadly towards the west, indicating that the spreading axis lay in that direction. The ophiolite north of the transform is much less extended, and we interpret this as a section of outside corner crust. In this interpretation, the Troodos ophiolite formed to the east (in its current orientation) of a ridge-transform-ridge intersection, in which the transform had a dextral offset and sinistral slip. The part of the ophiolite that forms the Limassol Forest was produced at the western inside corner, and spread eastward until it passed the second spreading axis, at which point the ophiolite north of the Arakapas Fault was created and welded to the Limassol Forest when the transform became a fracture zone.published_or_final_versio

How Should We Foster the Professional Integrity of Engineers in Japan? A Pride-Based Approach

I discuss the predicament that engineering-ethics education in Japan now faces and propose a solution to this. The predicament is professional motivation, i.e., the problem of how to motivate engineering students to maintain their professional integrity. The special professional responsibilities of engineers are often explained either as an implicit social contract between the profession and society (the “social-contract” view), or as requirements for membership in the profession (the “membership-requirement” view). However, there are empirical data that suggest that such views will not do in Japan, and this is the predicament that confronts us. In this country, the profession of engineering did not exist 10 years ago and is still quite underdeveloped. Engineers in this country do not have privileges, high income, or high social status. Under such conditions, neither the social-contract view nor the membership-requirement view is convincing. As an alternative approach that might work in Japan, I propose a pride-based view. The notion of pride has been analyzed in the virtue-ethics literature, but the full potential of this notion has not been explored. Unlike other kinds of pride, professional pride can directly benefit the general public by motivating engineers to do excellent work even without social rewards, since being proud of themselves is already a reward. My proposal is to foster a particular kind of professional pride associated with the importance of professional services in society, as the motivational basis for professional integrity. There is evidence to suggest that this model works

Assays to Detect β-Tubulin Codon 200 Polymorphism in Trichuris trichiura and Ascaris lumbricoides

The soil-transmitted helminths Ascaris lumbricoides and Trichuris trichiura are gastrointestinal nematodes causing many disabilities in tropical parts of the developing world. Control programs, such as “The Focussing Resources on Effective School Health” (FRESH) Partnership, have been implemented to remove human soil-transmitted nematodes through large-scale use of benzimidazole anthelmintic drugs for school-aged children in developing countries. The benzimidazole drugs albendazole and mebendazole are commonly used as a single annual treatment in areas where the burden is high. In veterinary nematodes, repeated use of these anthelmintics has selected for resistant populations. Resistance to benzimidazoles is commonly associated with a single amino acid substitution from phenylalanine to tyrosine in the β-tubulin gene at position 200. In this study, we have developed pyrosequencing assays for codon 200 in A. lumbricoides and T. trichiura to screen for this single nucleotide polymorphism (SNP) in β-tubulin. The 200Tyr SNP was detected at low frequency in T. trichiura from non-treated people from Kenya and at high frequency in T. trichiura from treated people from Panama. The presence of the resistance-associated SNP may play a role in the sometimes low and variable efficacy of benzimidazole anthelmintics against T. trichiura

A microtiter virus yield reduction assay for the evaluation of antiviral compounds against human cytomegalovirus and herpes simplex virus

Although the virus yield reduction assay is a powerful technique for evaluating the efficacy of antiviral compounds, it is not routinely utilized due to its labor-intensive nature. This procedure was modified, developed, thereby reducing greatly the time and effort required to perform yield reduction assays. Monolayer cultures of mammalian cells were grown in 96-well microtiter tissue culture plates and infected with virus. Test compounds were added and serially diluted directly with the plates. Following a cycle of virus replication, culture lysates were made and serially diluted in a separate set of uninfected cultures grown in microtiter plates. The cultures were incubated, plaques were enumerated in wells containing 5 to 20 plaques, and virus titers were calculated. To illustrate the use of the assay the known antiviral drugs acyclovir and ganciclovir were evaluated using this procedure. Ninety percent inhibitory concentrations for the respective drugs were 3 [mu]M and 0.7 [mu]M against herpes simplex virus type 1 and 60 [mu]M and 1 [mu]M against human cytomegalovirus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28636/1/0000450.pd

Annotation of two large contiguous regions from the Haemonchus contortus genome using RNA-seq and comparative analysis with Caenorhabditis elegans

The genomes of numerous parasitic nematodes are currently being sequenced, but their complexity and size, together with high levels of intra-specific sequence variation and a lack of reference genomes, makes their assembly and annotation a challenging task. Haemonchus contortus is an economically significant parasite of livestock that is widely used for basic research as well as for vaccine development and drug discovery. It is one of many medically and economically important parasites within the strongylid nematode group. This group of parasites has the closest phylogenetic relationship with the model organism Caenorhabditis elegans, making comparative analysis a potentially powerful tool for genome annotation and functional studies. To investigate this hypothesis, we sequenced two contiguous fragments from the H. contortus genome and undertook detailed annotation and comparative analysis with C. elegans. The adult H. contortus transcriptome was sequenced using an Illumina platform and RNA-seq was used to annotate a 409 kb overlapping BAC tiling path relating to the X chromosome and a 181 kb BAC insert relating to chromosome I. In total, 40 genes and 12 putative transposable elements were identified. 97.5% of the annotated genes had detectable homologues in C. elegans of which 60% had putative orthologues, significantly higher than previous analyses based on EST analysis. Gene density appears to be less in H. contortus than in C. elegans, with annotated H. contortus genes being an average of two-to-three times larger than their putative C. elegans orthologues due to a greater intron number and size. Synteny appears high but gene order is generally poorly conserved, although areas of conserved microsynteny are apparent. C. elegans operons appear to be partially conserved in H. contortus. Our findings suggest that a combination of RNA-seq and comparative analysis with C. elegans is a powerful approach for the annotation and analysis of strongylid nematode genomes

First assessment of the comparative toxicity of ivermectin and moxidectin in adult dung beetles: Sub-lethal symptoms and pre-lethal consequences

Among macrocyclic lactones (ML), ivermectin (IVM) and moxidectin (MOX) potentially affect all Ecdysozoan species, with dung beetles being particularly sensitive. The comparative effects of IVM and MOX on adult dung beetles were assessed for the first time to determine both the physiological sub-lethal symptoms and pre-lethal consequences. Inhibition of antennal response and ataxia were tested as two intuitive and ecologically relevant parameters by obtaining the lowest observed effect concentration (LOEC) values and interpolating other relevant toxicity thresholds derived from concentration-response curves (IC50, as the concentration of each ML where the antennal response is inhibited by half; and pLC50, as the quantity of ingested ML where partial paralysis was observed by half of treated individuals) from concentration-response curves. Both sub-lethal and pre-lethal symptoms obtained in this study coincided in that IVM was six times more toxic than MOX for adult dung beetles. Values of LOEC, IC50 and pLC50 obtained for IVM and MOX evaluated in an environmental context indicate that MOX, despite needing more time for its elimination in the faeces, would be half as harmful to dung beetles as IVM. This approach will be valuable to clarify the real impact of MLs on dung beetle health and to avoid the subsequent environmental consequences

A Research Agenda for Helminth Diseases of Humans: Health Research and Capacity Building in Disease-Endemic Countries for Helminthiases Control

Capacity building in health research generally, and helminthiasis research particularly, is pivotal to the implementation of the research and development agenda for the control and elimination of human helminthiases that has been proposed thematically in the preceding reviews of this collection. Since helminth infections affect human populations particularly in marginalised and low-income regions of the world, they belong to the group of poverty-related infectious diseases, and their alleviation through research, policy, and practice is a sine qua non condition for the achievement of the United Nations Millennium Development Goals. Current efforts supporting research capacity building specifically for the control of helminthiases have been devised and funded, almost in their entirety, by international donor agencies, major funding bodies, and academic institutions from the developed world, contributing to the creation of (not always equitable) North–South “partnerships”. There is an urgent need to shift this paradigm in disease-endemic countries (DECs) by refocusing political will, and harnessing unshakeable commitment by the countries' governments, towards health research and capacity building policies to ensure long-term investment in combating and sustaining the control and eventual elimination of infectious diseases of poverty. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. This paper discusses the challenges confronting capacity building for parasitic disease research in DECs, describes current capacity building strategies with particular reference to neglected tropical diseases and human helminthiases, and outlines recommendations to redress the balance of alliances and partnerships for health research between the developed countries of the “North” and the developing countries of the “South”. We argue that investing in South–South collaborative research policies and capacity is as important as their North–South counterparts and is essential for scaled-up and improved control of helminthic diseases and ultimately for regional elimination