Antimalarial chemotherapy: young guns or back to the future?

The burgeoning global problem of malaria is largely due to the emergence of parasite resistance to our limited armamentarium of antimalarial drugs. The recognition of this impending disaster at the international level and the engagement of the pharmaceutical industry promise a more optimistic future for antimalarial drug development. This is particularly exciting when considering the advances in our understanding of parasite biology, which are currently being fuelled by the malaria genome project. This article discusses recent developments in the area of antimalarial drug discovery and evaluation. New advances, based on traditional antimalarial drug classes including the quinolines, peroxides and antifolates (‘back to the future’), are discussed, followed by a presentation of some novel targets (‘young guns’) that have been shown to be good candidates for chemotherapeutic attack.     

Animal phylogeny: back to the coelomata?

The relationship between vertebrates and the principal model invertebrates - fruitflies and nematodes - is unclear. A fly-nematode grouping was becoming widely accepted, but recent comparisons of their genomes argue against this and link flies with the vertebrates instead.     

Anti-bacterial monoclonal antibodies: Back to the future?

Today's medicine has to deal with the emergence of multi-drug resistant bacteria, and is beginning to be confronted with pan-resistant microbes. This worsening inadequacy of the antibiotics concept, which has ruled infectious medicine in the last six decades creates an increasing unmet medical need that can be addressed by passive immunization. While past experience from the pre-antibiotic era with serum therapy was in many cases encouraging, antibacterial monoclonal antibodies have so far suffered high attrition rates in the clinic, generally from lack of efficacy. Yet, we believe that recent developments in a number of areas such as infectious disease pathogenesis research, translational medicine, mAb engineering, mAb manufacturing and rapid bedside diagnostics are converging to make the medium-term future permissive for antibacterial mAb development. Here, we review antibacterial mAb-based approaches that are or were in clinical development, and may potentially act as paradigms with regards to molecular targets, antibody formats and mode-of-action, pre-clinical validation and selection of most relevant patient populations, in order to increase the likelihood of successful product development in this field.     

Artificial chromosomes: a blueprint for the future?

Recent developments in molecular genetics have led to the synthesis of an artificial human chromosome. Because the chromosome replicates and divides normally in human cells, this has exciting possibilities in terms of mankind's ability to influence evolutionary processes and to modify the human genome.     

Immunological exhaustion: How to make a disparate concept operational?

In this essay, we show that 3 distinct approaches to immunological exhaustion coexist and that they only partially overlap, generating potential misunderstandings. Exploring cases ranging from viral infections to cancer, we propose that it is crucial, for experimental and therapeutic purposes, to clarify these approaches and their interconnections so as to make the concept of exhaustion genuinely operational.     

Why get big in the cold? Towards a solution to a life-history puzzle

The temperature–size rule (TSR), which states that body size increases at lower developmental temperatures, appears to be a near-universal law for ectotherms. Although recent studies seem to suggest that the TSR might be adaptive, the underlying developmental mechanisms are thus far largely unknown. Here, we investigate temperature effects on life-history traits, behaviour and physiology in the copper butterfly Lycaena tityrus in order to disentangle the mechanistic basis for the above rule. In L. tityrus the larger body size produced at a lower temperature was proximately due to a greater increase in mass, which was caused by both behavioural and physiological mechanisms: a much-increased food intake and a higher efficiency in converting ingested food into body matter. These mechanisms, combined with temperature-induced changes at the cellular level, may provide general explanations for the TSR. Body fat and protein content increased in butterflies reared at the higher temperature, indicating favourable growth conditions. As predicted from protandry theory, males showed reduced development times, caused by higher growth rates compared to females. The latter was itself related to a higher daily food consumption, while the total food consumption (due to the females’ longer developmental period) and assimilation was higher in females and may underly the sexual body size dimorphism.     

Australia's marine biogeography revisited: Back to the future?

The recognition of broad biogeographic provinces provides an important framework for ecological and conservation biological research. Marine biologists have long recognized distinct biogeographic provinces in southern Australia, primarily on the basis of qualitative differences in intertidal species assemblages. Here we provide an a priori test for these traditional eastern (Peronian), western (Flindersian) and south‐eastern (Maugean) provinces. Specifically, we analyse distributional data for approximately 1500 algal species using the newly available Australian Virtual Herbarium, an online database of herbarium specimens. Our quantitative algal analyses across southern Australia identify three distinct biogeographic assemblages, consistent with traditional qualitative provinces. We argue that these broad provinces provide a highly effective framework for understanding and managing Australia's marine biodiversity. In particular, biogeographic provinces provide a regional framework for integrating the ongoing discovery of biological variation at finer scales. More broadly therefore we recommend that biologists undertake quantitative analyses to test provincial biogeographic boundaries around the globe.     

Embryonic induction: Is the Nieuwkoop centre a useful concept?

Regionalisation of the amphibian embryo is classically thought to involve induction by the Spemann organiser, itself induced by the Nieuwkoop centre. This model has now been extended to teleosts, with the identification of a gene that appears to define the zebrafish equivalent of the Nieuwkoop centre.     

Marine metapopulations: a useful concept?

We discuss the potential and limitations of the metapopulation concept in marine ecology. The usefulness of the concept in terrestrial ecology is neither based on its simplicity or generality nor on overwhelming empirical evidence. The usefulness is in the questions which are asked when the metapopulation concept is applied. These questions address spatial phenomena and processes on different spatial scales. They help in acknowledging that every population, be it terrestrial or marine, has a spatial organization. Understanding this spatial organization is also important for tackling specific applied problems, i.e. to avoid overexploitation of living marine resources or for configuring marine reserves. The 'openness' of coastal populations, whose larvae enter larval pools or which are holoplanktonic, is no reason for not asking the questions implied by the metapopulation concept. For marine ecology, the real problem is to delineate populations, which then may possibly correspond to the 'local populations' of metapopulations. Thus, the answer to the question in the title of this paper, whether 'marine metapopulation' is a useful concept, is 'yes', if the concept is considered a working hypotheses, if the concept is explicitly defined, and if the questions linked to the concept are clearly stated. Even if it eventually transpires that only very few marine metapopulations actually exist, marine ecology would still have gained some important new insights. Electronic Publication     

Metallophytes—a view from the rhizosphere

Abundance of Fabaceae declines in representation through post-fire-succession in fynbos vegetation of the Cape Floristic Region (CFR). This reduction in legume occurrence coincides with a known decline in post-fire soil P availability. It was hypothesized that the disappearance of legume species during post-fire succession is due to an inability to acquire P effectively from sparingly soluble sources. P-acquisition strategies and response to P supply were compared between legume (Aspalathus, Cyclopia, Indigofera, Podalyria) and non-legume (Elegia, Leucadendron, Protea) genera when supplied with 1 or 10 mg P kg^?1 dry sand. Each genus consisted of a seeder (non-persistent) and resprouter (persistent) species. Non-legumes showed a greater investment in below-ground biomass, more root clusters, with higher concentrations of carboxylates exuded by cluster roots and carboxylates that were better suited to the mobilization of sparingly soluble P compared to legumes. The growth response to increased P supply was 53% higher in legumes than in non-legumes. The lack of a growth response to an elevated P supply in the non-legumes was attributed to N-limitation. Legume resprouters had a higher investment in cluster-root biomass and a lower capacity to down-regulate P-uptake than the seeders. Therefore the inability to acquire sufficient P from low concentration and sparingly soluble soil P-sources may contribute to the lack of indigenous legume persistence in fynbos vegetation of the CFR.     

Natural products as starting points for future anti-malarial therapies: going back to our roots?

Background

Population movements along the Thailand-Cambodia border, particularly among highly mobile and hard-to-access migrant groups from Cambodia and Myanmar, are assumed to play a key role in the spread of artemisinin resistance. Data on treatment-seeking behaviours, knowledge and perceptions about malaria, and use of preventive measures is lacking as characteristics of this population prevent them from being represented in routine surveillance and the lack of a sampling frame makes reliable surveys challenging.

Methods

A survey of migrant populations from Cambodia and Myanmar was implemented in five selected rural locations in Thailand along the Thai-Cambodian border using respondent driven sampling (RDS) to determine demographic characteristics of the population, migratory patterns, knowledge about malaria, and health-care -seeking behaviours.

Results

The majority of migrants from Myanmar are long-term residents (98%) with no plans to move back to Myanmar, understand spoken Thai (77%) and can therefore benefit from health messages in Thai, have Thai health insurance (99%) and accessed public health services in Thailand (63%) for their last illness. In comparison, the majority of Cambodian migrants are short-term (72%). Of the short-term Cambodian migrants, 92% work in agriculture, 18% speak Thai, 3.4% have Thai health insurance, and the majority returned to Cambodia for treatment (45%), self-treated (11%), or did not seek treatment for their last illness (27%).

Conclusion

Most highly mobile migrants along the Thai-Cambodia border are not accessing health messages or health treatment in Thailand, increasing their risk of malaria and facilitating the spread of potentially resistant Plasmodium falciparum as they return to Cambodia to seek treatment. Reaching out to highly mobile migrants with health messaging they can understand and malaria diagnosis and treatment services they can access is imperative in the effort to contain the spread of artemisinin-resistant P. falciparum.