Dates from the molecular clock: how wrong can we be?

Large discrepancies have been found in dates of evolutionary events obtained using the molecular clock. Twofold differences have been reported between the dates estimated from molecular data and those from the fossil record; furthermore, different molecular methods can give dates that differ 20-fold. New software attempts to incorporate appropriate allowances for this uncertainty into the calculation of the accuracy of date estimates. Here, we propose that these innovations represent welcome progress towards obtaining reliable dates from the molecular clock, but warn that they are currently unproven, given that the causes and pattern of the discrepancies are the subject of ongoing research. This research implies that many previous studies, even some of those using recently developed methods, might have placed too much confidence in their date estimates, and their conclusions might need to be revised.     

How does Anopheles gambiae kill malaria parasites?

The malaria parasite's lifecycle in the mosquito vector Anopheles gambiae involves several translocations within and between tissues during which large parasite losses have been documented. Interestingly, during the critical transition stages of midgut invasion and relocation of sporozoites from the oocysts to the salivary glands the mosquito innate immune system is activated. These defense reactions could, at least partially, be responsible for the parasite killing in the mosquito. This important question is now being approached by the dissection of the mosquito innate immune system as well as genetic and genomic studies.     

How malaria parasites reduce the deformability of infected red blood cells

The pathogenesis of malaria is largely due to stiffening of the infected red blood cells (RBCs). Contemporary understanding ascribes the loss of RBC deformability to a 10-fold increase in membrane stiffness caused by extra cross-linking in the spectrin network. Local measurements by micropipette aspiration, however, have reported only an increase of ～3-fold in the shear modulus. We believe the discrepancy stems from the rigid parasite particles inside infected cells, and have carried out numerical simulations to demonstrate this mechanism. The cell membrane is represented by a set of discrete particles connected by linearly elastic springs. The cytosol is modeled as a homogeneous Newtonian fluid, and discretized by particles as in standard smoothed particle hydrodynamics. The malaria parasite is modeled as an aggregate of particles constrained to rigid-body motion. We simulate RBC stretching tests by optical tweezers in three dimensions. The results demonstrate that the presence of a sizeable parasite greatly reduces the ability of RBCs to deform under stretching. With the solid inclusion, the observed loss of deformability can be predicted quantitatively using the local membrane elasticity measured by micropipettes.     

How can the complex epidemiology of malaria in India impact its elimination?

Malaria is a human health hazard in the tropical and subtropical zones of the globe and is poised to be eliminated by the year 2030. Despite a decrease in incidence in the past two decades, many endemic countries, including India, report cases regularly. The epidemiology of malaria in India is unique owing to several features of the Plasmodium parasites, Anopheles vectors, ecoepidemiological situations conducive to disease transmission, and susceptible humans living in rural and forested areas. Limitations in public health reach, and poor health-seeking behaviour of vulnerable populations living in hard-to-reach areas, add to the problem. We bring all of these factors together in a comprehensive framework and opine that, in spite of complexities, targeted elimination of malaria in India is achievable with planned programmatic approaches.     

Drug resistance in parasites: can we stay ahead of the evolutionary curve?

The articles in this special issue of Trends in Parasitology document the current status of drug discovery in various helminth and protozoan parasitic infections. Parasitic diseases present a unique challenge to those who try to prevent or treat them. In most cases, the parasite has evolved to evade the human immune system, so the human host can control, but not eliminate, the parasite. Design of effective vaccines against these diseases presents daunting difficulties; therefore, drugs are currently the only way to prevent or treat parasitic diseases. Under these circumstances, selection of resistance to any effective, well-tolerated drug is inevitable; the question is not if, but when. The goal of this review is to try to draw general conclusions about the measurement and selection of resistance to drugs directed against a variety of very different parasites.     

How much can we know about the causes of evolutionary trends?

One of the first questions that paleontologists ask when they identify a large-scale trend in the fossil record (e.g., size increase, complexity increase) is whether it is passive or driven. In this article, I explore two questions about driven trends: (1) what is the underlying cause or source of the directional bias? and (2) has the strength of the directional bias changed over time? I identify two underdetermination problems that prevent scientists from giving complete answers to these two questions.     

How reliably can we predict the reliability of protein structure predictions?

Background  

Comparative methods have been the standard techniques for in silico protein structure prediction. The prediction is based on a multiple alignment that contains both reference sequences with known structures and the sequence whose unknown structure is predicted. Intensive research has been made to improve the quality of multiple alignments, since misaligned parts of the multiple alignment yield misleading predictions. However, sometimes all methods fail to predict the correct alignment, because the evolutionary signal is too weak to find the homologous parts due to the large number of mutations that separate the sequences.     

How can molecular biology contribute to the management of congenital adrenal hyperplasia?

The most common form of congenital adrenal hyperplasia is due to a deficiency of 21-hydroxylase (21OHD) activity and is caused by a mutation in the CYP21 gene. By genotyping patients, new and important information can be gained, including presence or absence of 21OHD in borderline cases, determining the severity of disease and identifying heterozygote carriers. Current management of patients with 21OHD involves administering sufficient glucocorticoids to suppress excess adrenal androgen secretion, but not so much that bone growth and mineralization are impaired. New management strategies have been proposed and include administering only substitution doses of corticosteroids and counteracting side-effects by administering an anti-androgen and aromatase inhibitor. Adrenalectomy has also been proposed. Further investigation into these approaches is necessary.     

Resistance to xenobiotics and parasites: can we count the cost?

The nature and cost of single genes of major effect is one of the longest running controversies in biology. Resistance, whether to xenobiotics or to parasites, is often paraded as an obvious example of a single gene effect that must carry an associated fitness 'cost'. However, a review of the xenobiotic resistance literature shows that empirical evidence for this hypothesis is, in fact, scarce. We postulate that such fitness costs can only be fully interpreted in the light of the molecular mutations that might underlie them. We also derive a theoretical framework both to encompass our current understanding of xenobiotic resistance and to begin to dissect the probable cost of parasite resistance.     

How can we improve tracking of transplanted tissue in the United States?

Currently an estimated two million tissues are distributed for transplantation annually. With increasing use of recovered tissue, clusters of transplant-transmitted infection have shown the difficulty of tracking tissues from an infected donor to the recipient. The challenge of tissue tracking to multiple transplant recipients was illustrated in a recent investigation of transmission of hepatitis C virus infection from a donor of organs and tissues. When a tissue bank issued a recall of the donated tissue, the Centers for Disease Control and Prevention was notified to assist public health authorities; the mean time to locate and notify the physicians who had transplanted the tissue was 13 days, while the mean time to notify, inform, and test the patients was 29 days. Lack of common coding and nomenclature was one of the key challenges in tracking tissue to the recipient. Some changes that could improve timeliness in the event of a recall includes: (1) standardized tissue nomenclature and coding through unique donor identifiers; (2) tissue traceability requirements using systems similar to that used for blood products; (3) a surveillance system for adverse events that provides feedback at the provider level.     

How can we possibly resolve the planet's nitrogen dilemma?

Nitrogen is the most crucial element in the production of nutritious feeds and foods. The production of reactive nitrogen by means of fossil fuel has thus far been able to guarantee the protein supply for the world population. Yet, the production and massive use of fertilizer nitrogen constitute a major threat in terms of environmental health and sustainability. It is crucial to promote consumer acceptance and awareness towards proteins produced by highly effective microorganisms, and their potential to replace proteins obtained with poor nitrogen efficiencies from plants and animals. The fact that reactive fertilizer nitrogen, produced by the Haber Bosch process, consumes a significant amount of fossil fuel worldwide is of concern. Moreover, recently, the prices of fossil fuels have increased the cost of reactive nitrogen by a factor of 3 to 5 times, while international policies are fostering the transition towards a more sustainable agro-ecology by reducing mineral fertilizers inputs and increasing organic farming. The combination of these pressures and challenges opens opportunities to use the reactive nitrogen nutrient more carefully. Time has come to effectively recover used nitrogen from secondary resources and to upgrade it to a legal status of fertilizer. Organic nitrogen is a slow-release fertilizer, it has a factor of 2.5 or higher economic value per unit nitrogen as fertilizer and thus adequate technologies to produce it, for instance by implementing photobiological processes, are promising. Finally, it appears wise to start the integration in our overall feed and food supply chains of the exceptional potential of biological nitrogen fixation. Nitrogen produced by the nitrogenase enzyme, either in the soil or in novel biotechnology reactor systems, deserves to have a ‘renaissance’ in the context of planetary governance in general and the increasing number of people who desire to be fed in a sustainable way in particular.