PHAB toxins: a unique family of predatory sea anemone toxins evolving via intra-gene concerted evolution defines a new peptide fold

Sea anemone venoms have long been recognized as a rich source of peptides with interesting pharmacological and structural properties, but they still contain many uncharacterized bioactive compounds. Here we report the discovery, three-dimensional structure, activity, tissue localization, and putative function of a novel sea anemone peptide toxin that constitutes a new, sixth type of voltage-gated potassium channel (K_V) toxin from sea anemones. Comprised of just 17 residues, κ-actitoxin-Ate1a (Ate1a) is the shortest sea anemone toxin reported to date, and it adopts a novel three-dimensional structure that we have named the Proline-Hinged Asymmetric β-hairpin (PHAB) fold. Mass spectrometry imaging and bioassays suggest that Ate1a serves a primarily predatory function by immobilising prey, and we show this is achieved through inhibition of Shaker-type K_V channels. Ate1a is encoded as a multi-domain precursor protein that yields multiple identical mature peptides, which likely evolved by multiple domain duplication events in an actinioidean ancestor. Despite this ancient evolutionary history, the PHAB-encoding gene family exhibits remarkable sequence conservation in the mature peptide domains. We demonstrate that this conservation is likely due to intra-gene concerted evolution, which has to our knowledge not previously been reported for toxin genes. We propose that the concerted evolution of toxin domains provides a hitherto unrecognised way to circumvent the effects of the costly evolutionary arms race considered to drive toxin gene evolution by ensuring efficient secretion of ecologically important predatory toxins.     

Human fatalities caused by venomous animals in Utah, 1900-90

An examination of death certificates at the Utah Bureau of Health Statistics from 1900 through 1990 indicates that Utah has a very low incidence of human fatalities due to venomous bites and stings. During this 91-year period, 20 fatalities were recorded from bee (10) or hornet (1) stings, spider bites 94), and rattlesnake bites (5). There were eight additional fatalities during the early part of this century recorded "insect bite," "apparently insect bite," or "unknown agent poisoning," some of which may have included spiders. No deaths were recorded from Gila monster or scorpion evenomizations, although in 1962 one death in San Juan County was recorded as "venom poisoning, unknown agent, possible scorpion." Utah statistics follow the natural pattern, indicating that bee stings cause more fatalities than spider or rattlesnake bites. Raid deaths (within minutes) occurred in the majority of bee sting fatalities, resulting from allergic reactions (anaphylaxis), whereas protracted death times of days or months, resulting from infection, followed most spider or unknown insect bites. Only two spider bite fatalities occurred 1-3 days, suggesting black widow envenomization. Two of the five fatalities from rattlesnake bite resulted from handling the offending snake, one fatality was recorded as a homicide, and one other envenomization occurred in Arizona, with subsequent death in Utah.     

The situation of causality

Causality in the abstract is a grand theme. We take it up when we want to penetrate to the bottom of things to understand general laws that govern the working at the world of the deepest and most detailed level.In this essay, I argue for a more situated understanding of causality. To counter our desire for ever greater generality, I suggest that causal relations, even those that hold only on average, require context. To counter our desire for ever greater detail, I suggest that causal relations may exist only at a certain level of granularity.     

Indistinguishable photons from a single-photon device

Single-photon sources have recently been demonstrated using a variety of devices, including molecules, mesoscopic quantum wells, colour centres, trapped ions and semiconductor quantum dots. Compared with a Poisson-distributed source of the same intensity, these sources rarely emit two or more photons in the same pulse. Numerous applications for single-photon sources have been proposed in the field of quantum information, but most--including linear-optical quantum computation--also require consecutive photons to have identical wave packets. For a source based on a single quantum emitter, the emitter must therefore be excited in a rapid or deterministic way, and interact little with its surrounding environment. Here we test the indistinguishability of photons emitted by a semiconductor quantum dot in a microcavity through a Hong-Ou-Mandel-type two-photon interference experiment. We find that consecutive photons are largely indistinguishable, with a mean wave-packet overlap as large as 0.81, making this source useful in a variety of experiments in quantum optics and quantum information.     

Measuring the influence of individual data points in a cluster analysis

The problem of measuring the impact of individual data points in a cluster analysis is examined. The purpose is to identify those data points that have an influence on the resulting cluster partitions. Influence of a single data point is considered present when different cluster partitions result from the removal of the element from the data set. The Hubert and Arabie (1985) corrected Rand index was used to provide numerical measures of influence of a data point. Simulated data sets consisting of a variety of cluster structures and error conditions were generated to validate the influence measures. The results showed that the measure of internal influence was 100% accurate in identifying those data elements exhibiting an influential effect. The nature of the influence, whether beneficial or detrimental to the clustering, can be evaluated with the use of the gamma and point-biserial statistics.     

The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla

Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer. Hh signalling is mediated by its amino-terminal domain (HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle. Reception of the HhN signal is modulated by several cell-surface proteins on responding cells, including Patched (Ptc), Smoothened (Smo), Ihog (known as CDO or CDON in mammals) and the vertebrate-specific proteins Hip (also known as Hhip) and Gas1 (ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immunoglobulin and fibronectin type III (FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner. Surprisingly, pull-down experiments suggest that a mammalian Sonic hedgehog N-terminal domain (ShhN) binds a non-orthologous FNIII repeat of CDO. Here we report biochemical, biophysical and X-ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN-CDO interaction is completely unlike the HhN-Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners.