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.     

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.     

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.     

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.     

Nitrogen and carbon storage in alpine plants

Alpine plants offer unique opportunities to study the processesand economics of nutrient storage. The short alpine growingseason forces rapid completion of plant growth cycles, whichin turn causes competition between vegetative and reproductivegrowth sinks during the early part of the growing season. Mobilizationof stored nitrogen and carbon reserves facilitates competingsinks and permits successful completion of reproduction beforethe onset of winter stress. We discuss the theoretical frameworkfor assessing the costs and benefits of nutrient storage inalpine plants in order to lay the foundation for interpretationof observations. A principal point that has emerged from pasttheoretical treatments is the distinction between reserve storage,defined as storage that occurs with a cost to growth, and resourceaccumulation, defined as storage that occurs when resource supplyexceeds demand, and thus when there is no cost to growth. Wethen discuss two case studies, one already published and onenot yet published, pertaining to the storage and utilizationof nitrogen and carbon compounds in alpine plants from NiwotRidge, Colorado. In the first case, we tested the hypothesisthat the seasonal accumulation of amino acids in the rhizomeof N-fertilized plants of Bistorta bistortoides provides anadvantage to the plant by not imposing a cost to growth at thetime of accumulation, but providing a benefit to growth whenthe accumulated N is remobilized. We show that, as predicted,there is no cost during N accumulation but, not as predicted,there is no benefit to future growth. In the presence of N accumulation,reliance on stored N for growth increases, but reliance on current-season,soil-derived N decreases; thus the utilization of availableN in this species is a ‘zero sum’ process. Inherentmeristematic constraints to growth cause negative feedback thatlimits the utilization of accumulated N and precludes long-termadvantages to this form of storage. In the second case study,we discuss new results showing high concentrations of cyclicpolyol (cyclitol) compounds in the leaves of many alpine speciesdominant in the dry fellfield habitat. In Artemisia scopulorum,cyclitols were induced as the growing season progressed, andreached highest concentrations during the dry, late-summer months.Leaf cyclitol concentrations were high in all four species ofthe Caryophyllaceae that we examined and appeared to be constitutivecomponents of the leaf carbohydrate pool as concentrations werehigh through the entire growing season. We observed correlationsamong seedling abundance, seeding survivorship and the presenceof high leaf cyclitol concentrations. We propose that the primaryfunction of cyclitols in the leaves of alpine, fellfield herbsis to promote drought tolerance through osmotic protection,and enhance fitness by improving seedling survival. We consideredthe possibility that cyclitols also function as carbon storagecompounds that are remobilized at the end of the growing seasonand used to support growth the following year. Our observationsdo not support this hypothesis in the Caryophyllaceae becausethe requirement for high constitutive concentrations year-after-yearprevents long-term advantages of storage and remobilization.However, in A. scopulorum, remobilization of cyclitols followingthe end of the growing season may provide storage substratesthat can be used for growth the following season. From our analysiswe conclude that it is difficult to use current theory thatis embedded in the economic concept of costs and benefits tointerpret observed dynamics in nitrogen and carbon allocation.Future theoretical developments that move away from an abstractfoundation embedded in cost-benefit tradeoffs and toward phenotypicintegration of source-sink relationships will improve our abilityto merge observations and theory.     

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.     

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.     

The detection of estrus in cattle raised under tropical conditions: what we know and what we need to know

Lack of accuracy in estrus detection in cattle is a major constraint affecting the implementation of techniques such as artificial insemination (AI) and embryo transfer (ET). For this reason clinicians have opted to pharmacologically manipulate the estrus cycle. The advantages and shortcomings of using this approach to improve the implementation of AI and ET are discussed in this review. Moreover, in order to highlight the reasons why estrus detection is difficult in cows kept at grazing in the tropics, this review underlines social and behavioral traits hindering the capacity of the casual observer to accurately identify cows in estrus.     

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.