Evidence for selection on coloration in a Panamanian poison frog: a coalescent-based approach

Aim The strawberry poison frog, Oophaga pumilio, has undergone a remarkable radiation of colour morphs in the Bocas del Toro archipelago in Panama. This species shows extreme variation in colour and pattern between populations that have been geographically isolated for < 10,000 years. While previous research has suggested the involvement of divergent selection, to date no quantitative test has examined this hypothesis. Location Bocas del Toro archipelago, Panama. Methods We use a combination of population genetics, phylogeography and phenotypic analyses to test for divergent selection in coloration in O. pumilio. Tissue samples of 88 individuals from 15 distinct populations were collected. Using these data, we developed a gene tree using the mitochondrial DNA (mtDNA) d-loop region. Using parameters derived from our mtDNA phylogeny, we predicted the coalescence of a hypothetical nuclear gene underlying coloration. We collected spectral reflectance and body size measurements on 94 individuals from four of the populations and performed a quantitative analysis of phenotypic divergence. Results The mtDNA d-loop tree revealed considerable polyphyly across populations. Coalescent reconstructions of gene trees within population trees revealed incomplete genotypic sorting among populations. The quantitative analysis of phenotypic divergence revealed complete lineage sorting by colour, but not by body size: populations showed non-overlapping variation in spectral reflectance measures of body coloration, while variation in body size did not separate populations. Simulations of the coalescent using parameter values derived from our empirical analyses demonstrated that the level of sorting among populations seen in colour cannot reasonably be attributed to drift. Main conclusions These results imply that divergence in colour, but not body size, is occurring at a faster rate than expected under neutral processes. Our study provides the first quantitative support for the claim that strong diversifying selection underlies colour variation in the strawberry poison frog.

Early bursts of body size and shape evolution are rare in comparative data

George Gaylord Simpson famously postulated that much of life's diversity originated as adaptive radiations-more or less simultaneous divergences of numerous lines from a single ancestral adaptive type. However, identifying adaptive radiations has proven difficult due to a lack of broad-scale comparative datasets. Here, we use phylogenetic comparative data on body size and shape in a diversity of animal clades to test a key model of adaptive radiation, in which initially rapid morphological evolution is followed by relative stasis. We compared the fit of this model to both single selective peak and random walk models. We found little support for the early-burst model of adaptive radiation, whereas both other models, particularly that of selective peaks, were commonly supported. In addition, we found that the net rate of morphological evolution varied inversely with clade age. The youngest clades appear to evolve most rapidly because long-term change typically does not attain the amount of divergence predicted from rates measured over short time scales. Across our entire analysis, the dominant pattern was one of constraints shaping evolution continually through time rather than rapid evolution followed by stasis. We suggest that the classical model of adaptive radiation, where morphological evolution is initially rapid and slows through time, may be rare in comparative data.

Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2-3 wk after weaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention.

Trial history biases the spatial programming of antisaccades

The historical context in which saccades are made influences their latency and error rates, but less is known about how context influences their spatial parameters. We recently described a novel spatial bias for antisaccades, in which the endpoints of these responses deviate towards alternative goal locations used in the same experimental block, and showed that expectancy (prior probability) is at least partly responsible for this 'alternate-goal bias'. In this report we asked whether trial history also plays a role. Subjects performed antisaccades to a stimulus randomly located on the horizontal meridian, on a 40° angle downwards from the horizontal meridian, or on a 40° upward angle, with all three locations equally probable on any given trial. We found that the endpoints of antisaccades were significantly displaced towards the goal location of not only the immediately preceding trial (n - 1) but also the penultimate (n - 2) trial. Furthermore, this bias was mainly present for antisaccades with a short latency of <250 ms and was rapidly corrected by secondary saccades. We conclude that the location of recent antisaccades biases the spatial programming of upcoming antisaccades, that this historical effect persists over many seconds, and that it influences mainly rapidly generated eye movements. Because corrective saccades eliminate the historical bias, we suggest that the bias arises in processes generating the response vector, rather than processes generating the perceptual estimate of goal location.

The word-length effect in acquired alexia, and real and virtual hemianopia

A word-length effect is often described in pure alexia, with reading time proportional to the number of letters in a word. Given the frequent association of right hemianopia with pure alexia, it is uncertain whether and how much of the word-length effect may be attributable to the hemifield loss. To isolate the contribution of the visual field defect, we simulated hemianopia in healthy subjects with a gaze-contingent paradigm during an eye-tracking experiment. We found a minimal word-length effect of 14 ms/letter for full-field viewing, which increased to 38 ms/letter in right hemianopia and to 31 ms/letter in left hemianopia. We found a correlation between mean reading time and the slope of the word-length effect in hemianopic conditions. The 95% upper prediction limits for the word-length effect were 51 ms/letter in subjects with full visual fields and 161 ms/letter with simulated right hemianopia. These limits, which can be considered diagnostic criteria for an alexic word-length effect, were consistent with the reading performance of six patients with diagnoses based independently on perimetric and imaging data: two patients with probable hemianopic dyslexia, and four with alexia and lesions of the left fusiform gyrus, two with and two without hemianopia. Two of these patients also showed reduction of the word-length effect over months, one with and one without a reading rehabilitation program. Our findings clarify the magnitude of the word-length effect that originates from hemianopia alone, and show that the criteria for a word-length effect indicative of alexia differ according to the degree of associated hemifield loss.

Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes

Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials.

What is the evidence supporting the prevention of osteoarthritis and improved femoral coverage after shelf procedure for Legg-Calvé-Perthes disease?

The evidence supporting continued use of shelf acetabuloplasty in Legg-Calvé-Perthes disease (LCPD) is not well-defined, and there is controversy regarding the long-term benefits related to clinical and functional improvement.

Learning from failure--rationale and design for a study about discontinuation of randomized trials (DISCO study)

Background Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. Methods/Design Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs. We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. Discussion Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

The transcription factor encyclopedia

Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field.