Chagas heart disease pathogenesis: one mechanism or many?

Chagas heart disease (CHD), caused by the protozoan parasite Trypanosoma cruzi, is the leading cause of infectious myocarditis in the world. The etiology of CHD is unclear and multiple mechanisms have been proposed to explain the pathogenesis of the disease. This review describes the proposed mechanisms of CHD pathogenesis and evaluates the historical significance and evidence supporting each. Although the majority of CHD-related pathologies are currently attributed to parasite persistence in the myocardium and autoimmunity, there is strong evidence that CHD develops as a result of additive and even synergistic effects of several distinct mechanisms rather than one factor.     

Nucleosome remodeling: one mechanism, many phenomena?

The term 'nucleosome remodeling' subsumes a large number of energy-dependent alterations of canonical nucleosome structure, catalyzed by dedicated ATPases in large multiprotein complexes. The importance of these factors for gene regulation and other processes with chromatin substrate have emerged from genetic studies. Mechanistic analyses of nucleosome remodeling by different enzymes provided a diverse, almost confusing phenomenology of ATP-dependent derangement of nucleosomes in vitro, suggesting that different remodeling machines follow different strategies to disrupt histone-DNA interactions. This review explores the alternative possibility that the rich phenomenology of nucleosome remodeling may be brought about by variations of one basic remodeling reaction.     

From stem cell to T cell: one route or many?

T cells developing in the adult thymus ultimately derive from haematopoietic stem cells in the bone marrow. Here, we summarize research into the identity of the haematopoietic progenitors that leave the bone marrow, migrate through the blood and settle in the thymus to generate T cells. Accumulating data indicate that various different bone-marrow progenitors are T-cell-lineage competent and might contribute to intrathymic T-cell development. Such developmental flexibility implies a mechanism of T-cell-lineage commitment that can operate on a range of T-cell-lineage-competent progenitors, and further indicates that only those T-cell-lineage-competent progenitors able to migrate to, and settle in, the thymus should be considered physiological T-cell progenitors.     

Head-tail patterning of the vertebrate embryo: one, two or many unresolved problems?

When, where and how is the head-tail axis of the embryo set up during development? These are such fundamental and intensely studied questions that one might expect them to have been answered long ago. Not so; we still understand very little about the cellular or molecular mechanisms that lead to the orderly arrangement of body elements along the head-tail axis in vertebrates. In this paper, we outline some of the major outstanding problems and controversies and try to identify some reasons why it has been so difficult to resolve this important issue.     

The willow bud galler Euura mucronata Hartig (Hymenoptera: Tenthredinidae): one polyphage or many monophages?

The nematine sawfly Euura mucronata Hartig (Hymenoptera: Tenthredinidae) induces galls in the buds of over 30 willow species across the Holarctic region. This extensive host range is surprising, since the other Euura gallers are mostly monophagous; thus, the feeding habit of E. mucronata would represent a switch from monophagy to extreme polyphagy. Previous morphological studies have divided E. mucronata into separate species, but the feeding ranges of these species are unknown, and it is even doubtful whether multiple species really exist. To study whether or not E. mucronata consists of cryptic host-associated sibling species, an allozyme study was conducted using gallers collected from six willow species occurring in northern Fennoscandia. Electrophoretic data from seven variable enzyme loci show that: (1) "E. mucronata" probably comprises at least three species with restricted host ranges, but the species may not be completely reproductively isolated from each other; (2) the pattern of host use is not explained by the phylogeny of willows; (3) the pattern of host use is not concordant with the overall chemical similarity of the hosts; and (4) simple allopatric speciation does not appear to explain the host associations. Consequently, it is possible that reasons such as differences in host phenology, habitat, or morphology, are responsible for the limits in host use in the group.     

Cell death: programmed, apoptosis, necrosis, or other?

There are at least two major types of active or physiological cell death. The most well-known form, apoptosis or Type I, involves early nuclear collapse, condensation of chromatin, generation of nucleosomal ladders, and cell fragmentation with little or no early alteration of lysosomes. It is most commonly seen in cells deriving from highly mitotic lines, and the cells are phagocytosed by neighboring cells or infiltrating macrophages. In metamorphosing or secretory cells, and under conditions where the majority of cells die, the bulk of the cytoplasm is consumed by expansion of the lysosomal system well before nuclear collapse is manifest. This form of cell death has been termed Type II cell death, and we revert to this terminology. The requirement for protein synthesis is more characteristic of Type II cell death in developmental situations than it is for Type I cell death. The variations seen force a reassessment of those aspects of physiological cell death that are truly universal, thereby focusing attention on the biology of the process. A better understanding of the biology and morphology of dying cells will help clarify the significance of the molecular and biochemical findings.     

The roles of interleukin-15 receptor alpha: trans-presentation, receptor component, or both?

Interleukin-15 receptor alpha (IL-15R alpha) is a high affinity IL-15 binding protein that is crucial for mediating IL-15 functions such as memory CD8 T cell proliferation and NK, NK/T cell, and intestinal intraepithelial lymphocyte development. However, the mechanism by which IL-15R alpha mediates IL-15 functions is unique among cytokines. Originally, IL-15R alpha was thought to be a component of a heterotrimeric receptor complex containing the IL-2/IL-15R beta and common gamma chains (gammaC) that were required for mediating signaling. Although IL-15R alpha may in some cases act as a component of this receptor complex, more recent evidence indicates that IL-15R alpha predominately functions by presenting IL-15 to opposing cells expressing the IL-15R betagamma signaling components. This theory is consistent with the broad, non-lymphoid expression pattern of IL-15R alpha and the evidence that IL-15R alpha expression by lymphocytes is dispensable for IL-15 action in vivo. This new concept of cytokine delivery will allow us to better understand the regulation and function IL-15.     

ABC transporters: one,two or four extracytoplasmic substrate-binding sites?

Two families of ATP-binding cassette (ABC) transporters in which one or two extracytoplasmic substrate-binding domains are fused to either the N- or C-terminus of the translocator protein have been detected. This suggests that two, or even four, substrate-binding sites may function in the ABC transporter complex. This domain organization in ABC transporters, widely represented among microorganisms, raises new possibilities for how the substrate-binding protein(s) (SBPs) might interact with the translocator. One appealing hypothesis is that multiple substrate-binding sites in proximity to the entry site of the translocation pore enhance the transport capacity. We also discuss the implications of multiple substrate-binding sites in close proximity to the translocator in terms of broadened substrate specificity and possible cooperative interactions between SBPs and the translocator.     

HIF-2α: Many cancers,one engine?

Comment on: Franovic A, et al. Human cancers converge at the HIF-2α oncogenic axis. Proc Natl Acad Sci USA 2009; 106:21306-11.     

Planar cell polarity: one or two pathways?

In multicellular organisms, cells are polarized in the plane of the epithelial sheet, revealed in some cell types by oriented hairs or cilia. Many of the underlying genes have been identified in Drosophila melanogaster and are conserved in vertebrates. Here we dissect the logic of planar cell polarity (PCP). We review studies of genetic mosaics in adult flies - marked cells of different genotypes help us to understand how polarizing information is generated and how it passes from one cell to another. We argue that the prevailing opinion that planar polarity depends on a single genetic pathway is wrong and conclude that there are (at least) two independently acting processes. This conclusion has major consequences for the PCP field.