The origin of life: what we know,what we can know and what we will never know

The origin of life (OOL) problem remains one of the more challenging scientific questions of all time. In this essay, we propose that following recent experimental and theoretical advances in systems chemistry, the underlying principle governing the emergence of life on the Earth can in its broadest sense be specified, and may be stated as follows: all stable (persistent) replicating systems will tend to evolve over time towards systems of greater stability. The stability kind referred to, however, is dynamic kinetic stability, and quite distinct from the traditional thermodynamic stability which conventionally dominates physical and chemical thinking. Significantly, that stability kind is generally found to be enhanced by increasing complexification, since added features in the replicating system that improve replication efficiency will be reproduced, thereby offering an explanation for the emergence of life''s extraordinary complexity. On the basis of that simple principle, a fundamental reassessment of the underlying chemistry–biology relationship is possible, one with broad ramifications. In the context of the OOL question, this novel perspective can assist in clarifying central ahistoric aspects of abiogenesis, as opposed to the many historic aspects that have probably been forever lost in the mists of time.     

Correlates of immune protection in HIV-1 infection: what we know, what we don't know, what we should know

The field of vaccinology began in ignorance of how protection was instilled in vaccine recipients. Today, a greater knowledge of immunology allows us to better understand what is being stimulated by various vaccines that leads to their protective effects: that is, their correlates of protection. Here we describe what is known about the correlates of protection for existing vaccines against a range of different viral diseases and discuss the correlates of protection against disease during natural infection with HIV-1. We will also discuss why it is important to design phase 3 clinical trials of HIV vaccines to determine the correlates of protection for each individual vaccine.     

Membrane fission by dynamin: what we know and what we need to know

The large GTPase dynamin is the first protein shown to catalyze membrane fission. Dynamin and its related proteins are essential to many cell functions, from endocytosis to organelle division and fusion, and it plays a critical role in many physiological functions such as synaptic transmission and muscle contraction. Research of the past three decades has focused on understanding how dynamin works. In this review, we present the basis for an emerging consensus on how dynamin functions. Three properties of dynamin are strongly supported by experimental data: first, dynamin oligomerizes into a helical polymer; second, dynamin oligomer constricts in the presence of GTP; and third, dynamin catalyzes membrane fission upon GTP hydrolysis. We present the two current models for fission, essentially diverging in how GTP energy is spent. We further discuss how future research might solve the remaining open questions presently under discussion.     

The Drosophila circadian clock: what we know and what we don't know.

Circadian rhythms are regulated by endogenous body clocks, which are formed by rhythmic cycles of clock gene expression. Almost all reviews of the Drosophila circadian clock state that the intracellular oscillator is based on a simple negative feedback loop. However, not many 'simple' feedback loops in biology last for 24 h. Instead, the Drosophila clock is a series of precisely timed steps that are deliberately slow. In this paper, I will discuss the current model for how the Drosophila clock is regulated, and ask what questions remain to be answered.     

Polydomy in ants: what we know, what we think we know, and what remains to be done

The correct identification of colony boundaries is an essential prerequisite for empirical studies of ant behaviour and evolution. Ant colonies function at various organizational levels, and these boundaries may be difficult to assess. Moreover, new complexity can be generated through the presence of spatially discrete subgroups within a more or less genetically homogeneous colony, a situation called polydomy. A colony is polydomous only if individuals (workers and brood) of its constituent nests function as a social and cooperative unit and are regularly interchanged among nests. This condition was previously called polycalic, and the term polydomy was used in a broader sense for a group of daughter nests of the same mother colony (implying limited female dispersal), without regard to whether these different nests continued to exchange individuals. We think that this distinction between ‘polycaly’ and ‘polydomy’ concerns two disparate concepts. We thus prefer the narrower definition of polydomy, which groups individuals that interact socially. Does this new level of organization affect the way in which natural selection acts on social traits? Here, after examining the history of terms, we review all ant species that have been described as expressing polydomous structures. We show that there is no particular syndrome of traits predictably associated with polydomy. We detail the existing theoretical predictions and empirical results on the ecology of polydomy, and the impact of polydomy on social evolution and investment strategies, while carefully distinguishing monogynous from polygynous species. Finally, we propose a methodology for future studies and offer ideas about what remains to be done. © 2007 The Linnean Society of London, Biological Journal of the Linnean Society, 2007, 90 , 319–348.     

Breast cancer genetics: what we know and what we need

Breast cancer results from genetic and environmental factors leading to the accumulation of mutations in essential genes. Genetic predisposition may have a strong, almost singular effect, as with BRCA1 and BRCA2, or may represent the cumulative effects of multiple low-penetrance susceptibility alleles. Here we review high- and low-penetrance breast-cancer-susceptibility alleles and discuss ongoing efforts to identify additional susceptibility genes. Ultimately these discoveries will lead to individualized breast cancer risk assessment and a reduction in breast cancer incidence.     

Farnesoid secretions of dipteran ring glands: what we do know and what we can know

Harnessing of the Drosophila genetic system toward ascertaining the molecular endocrinology of higher dipteran (cyclorrhaphan) larval development has been a goal for over 70 years, beginning with the data left to us by pioneer researchers from the classical endocrine era. The results of their experiments evidence numerous ring gland activities that are parsimoniously explained as arising from secretions of the larval corpora allatal cells. Utilization of those data toward an understanding of molecular endocrinology of cyclorrhaphan metamorphosis has not yet achieved its hoped for fruition, in part due to a perceived difficulty in identifying larval targets of the molecule "methyl epoxyfarnesoate" (=juvenile hormone III). However, as is reviewed here, it is important to maintain a conceptual distinction between "the target of JH III"Versus "the target(s) of products secreted by the larval corpora allatal cells of ring glands." Recent advances have been made on the identity, regulation and reception of ring gland farnesoid products. When these advances are evaluated together with the above data from the classical endocrine era, there is a new opportunity to frame experimental hypotheses so as to discern underlying mechanisms on cyclorrhaphan larval-pupal metamorphosis that have been heretofore intractable. This paper reconsiders a number of evidenced physiological targets of secretions of corpora allatal cells of the larval ring gland, and places them in the context of more recent biochemical and molecular advances in the field.     

Mechanisms of atrial fibrillation in athletes: what we know and what we do not know

Exercise is an emerging cause of atrial fibrillation (AF) in young individuals without coexisting cardiovascular risk factors. The causes of exercise-induced atrial fibrillation remain largely unknown, and conclusions are jeopardised by apparently conflicting data. Some components of the athlete’s heart are known to be arrhythmogenic in other settings. Bradycardia, atrial dilatation and, possibly, atrial premature beats are therefore biologically plausible contributors to exercise-induced AF. Challenging findings in an animal model suggest that exercise might also prompt the development of atrial fibrosis, possibly due to cumulative minor structural damage after each exercise bout. However, there is very limited, indirect data supporting this hypothesis in athletes. Age, sex, the presence of comorbidities and cardiovascular risk factors, and genetic individual variability might serve to flag those athletes who are at the higher risk of exercise-induced AF. In this review, we will critically address current knowledge on the mechanisms of exercise-induced AF.     

Deciphering the Leishmania exoproteome: what we know and what we can learn

Parasitic protozoa of the genus Leishmania are the causative agents of leishmaniasis. Survival and transmission of these parasites in their different hosts require membrane-bound or extracellular factors to interact with and modify their host environments. Over the last decade, several approaches have been applied to study all the extracellular proteins exported by an organism at a particular time or stage in its life cycle and under defined conditions, collectively termed the secretome or the exoproteome. In this review, we focus on emerging data shedding light on the secretion mechanisms involved in the production of the Leishmania exoproteome. We also describe other methodologies currently available that could be used to analyse the Leishmania exoproteome. Understanding the complexity of the Leishmania exoproteome is a key component to elucidating the mechanisms used by these parasites for exporting proteins to the extracellular space during its life cycle. Given the importance of extracellular factors, a detailed knowledge of the Leishmania exoproteome may provide novel targets for rational drug design and/or a source of antigens for vaccine development.     

ATP synthase: what we know about ATP hydrolysis and what we do not know about ATP synthesis

In ATP synthase, X-ray structures, demonstration of ATP-driven gamma-subunit rotation, and tryptophan fluorescence techniques to determine catalytic site occupancy and nucleotide binding affinities have resulted in pronounced progress in understanding ATP hydrolysis, for which a mechanism is presented here. In contrast, ATP synthesis remains enigmatic. The molecular mechanism by which ADP is bound in presence of a high ATP/ADP concentration ratio is a fundamental unknown; similarly P(i) binding is not understood. Techniques to measure catalytic site occupancy and ligand binding affinity changes during net ATP synthesis are much needed. Relation of these parameters to gamma-rotation is a further goal. A speculative model for ATP synthesis is offered.     

Amphibian decline and extinction: what we know and what we need to learn

For over 350 million yr, thousands of amphibian species have lived on Earth. Since the 1980s, amphibians have been disappearing at an alarming rate, in many cases quite suddenly. What is causing these declines and extinctions? In the modern era (post 1500) there are 6 leading causes of biodiversity loss in general, and all of these acting alone or together are responsible for modern amphibian declines: commercial use; introduced/exotic species that compete with, prey on, and parasitize native frogs and salamanders; land use change; contaminants; climate change; and infectious disease. The first 3 causes are historical in the sense that they have been operating for hundreds of years, although the rate of change due to each accelerated greatly after about the mid-20th century. Contaminants, climate change, and emerging infectious diseases are modern causes suspected of being responsible for the so-called 'enigmatic decline' of amphibians in protected areas. Introduced/exotic pathogens, land use change, and infectious disease are the 3 causes with a clear role in amphibian decline as well as extinction; thus far, the other 3 causes are only implicated in decline and not extinction. The present work is a review of the 6 causes with a focus on pathogens and suggested areas where new research is needed. Batrachochytrium dendrobatidis (Bd) is a chytrid fungus that is an emerging infectious disease causing amphibian population decline and species extinction. Historically, pathogens have not been seen as a major cause of extinction, but Bd is an exception, which is why it is such an interesting, important pathogen to understand. The late 20th and early 21st century global biodiversity loss is characterized as a sixth extinction event. Amphibians are a striking example of these losses as they disappear at a rate that greatly exceeds historical levels. Consequently, modern amphibian decline and extinction is a lens through which we can view the larger story of biodiversity loss and its consequences.