Balancing the robustness and predictive performance of biomarkers.

Recent studies have highlighted the importance of assessing the robustness of putative biomarkers identified from experimental data. This has given rise to the concept of stable biomarkers, which are ones that are consistently identified regardless of small perturbations to the data. Since stability is not by itself a useful objective, we present a number of strategies that combine assessments of stability and predictive performance in order to identify biomarkers that are both robust and diagnostically useful. Moreover, by wrapping these strategies around logistic regression classifiers regularized by the elastic net penalty, we are able to assess the effects of correlations between biomarkers upon their perceived stability. We use a synthetic example to illustrate the properties of our proposed strategies. In this example, we find that: (i) assessments of stability can help to reduce the number of false-positive biomarkers, although potentially at the cost of missing some true positives; (ii) combining assessments of stability with assessments of predictive performance can improve the true positive rate; and (iii) correlations between biomarkers can have adverse effects on their stability and hence must be carefully taken into account when undertaking biomarker discovery. We then apply our strategies in a proteomics context to identify a number of robust candidate biomarkers for the human disease HTLV1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

Genes Suggest Ancestral Colour Polymorphisms Are Shared across Morphologically Cryptic Species in Arctic Bumblebees

email Suzanne orcd idCopyright: © 2015 Williams et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Modified differentials and basic cohomology for Riemannian foliations

We define a new version of the exterior derivative on the basic forms of a Riemannian foliation to obtain a new form of basic cohomology that satisfies Poincar\'e duality in the transversally orientable case. We use this twisted basic cohomology to show relationships between curvature, tautness, and vanishing of the basic Euler characteristic and basic signature.Comment: 20 pages, references added, minor corrections mad

Beyond knowing nature: Contact, emotion, compassion, meaning, and beauty are pathways to nature connection

Feeling connected to nature has been shown to be beneficial to wellbeing and pro-environmental behaviour. General nature contact and knowledge based activities are often used in an attempt to engage people with nature. However the specific routes to nature connectedness have not been examined systematically. Two online surveys (total n = 321) of engagement with, and value of, nature activities structured around the nine values of the Biophila Hypothesis were conducted. Contact, emotion, meaning, and compassion, with the latter mediated by engagement with natural beauty, were predictors of connection with nature, yet knowledge based activities were not. In a third study (n = 72), a walking intervention with activities operationalising the identified predictors, was found to significantly increase connection to nature when compared to walking in nature alone or walking in and engaging with the built environment. The findings indicate that contact, emotion, meaning, compassion, and beauty are pathways for improving nature connectedness. The pathways also provide alternative values and frames to the traditional knowledge and identification routes often used by organisations when engaging the public with nature.N/

Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain

Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord. Selective spinal nerve ligation (SNL) in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days) significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P < 0.001). Minocycline treatment also significantly attenuated OX-42 immunoreactivity, a marker of activated microglia, in the ipsilateral (P < 0.001) and contralateral (P < 0.01) spinal cord of SNL rats, compared to vehicle controls. Minocycline treatment significantly (P < 0.01) decreased levels of 2-AG and significantly (P < 0.01) increased levels of PEA in the ipsilateral spinal cord of SNL rats, compared to the contralateral spinal cord. Thus, activation of microglia affects spinal levels of endocannabinoids and related compounds in neuropathic pain states

Non-strategic ignorance: Considering the potential for a paradigm shift in evidence-based mental health

Randomised controlled trials form a central building block within the prevailing evidence-based mental health paradigm. Both methodology and paradigm have been widely problematised since their emergence in the mid-late twentieth century. We draw on the concept of ‘strategic ignorance’ to understand why the paradigm still prevails. We present focus group data gathered from 37 participants (service users, public, carers, general practitioners, commissioners) concerning the way they made sense of a randomised controlled trial of psychotherapy for treatment-resistant depression. Thematic analysis of the findings revealed an overall critique of randomised controlled trial methods which we refer to as ‘non-strategic ignorance’. Specifically, participants problematised the construct of depression, unseating the premise of the randomised controlled trial; they were sceptical about the purpose and highlighted its failure to show how therapy works or who might benefit; the randomised controlled trial was seen as inadequate for informing decisions about how to select a therapy. Participants assumed the treatment would be cost-effective given the client group and nature of the therapy, irrespective of any randomised controlled trial findings. Each area of lay (‘non-strategic’) critique has an analogous form within the methodological expert domain. We argue that ‘expert’ critiques have generally failed to have paradigmatic impact because they represent strategic ignorance. Yet parallel non-strategic critiques have common sense appeal, highlighting the potential power of lay voices. The discussion considers whether the evidence-based mental health paradigm is faced with epistemological problems of such complexity that the conditions exist for a new paradigm in which service user views are central and randomised controlled trials peripheral

The spine of the swan: A Herschel study of the DR21 ridge and filaments in Cygnus X

In order to characterise the cloud structures responsible for the formation of high-mass stars, we present Herschel observations of the DR21 environment. Maps of the column density and dust temperature unveil the structure of the DR21 ridge and several connected filaments. The ridge has column densities larger than 1e23/cm^2 over a region of 2.3 pc^2. It shows substructured column density profiles and branching into two major filaments in the north. The masses in the studied filaments range between 130 and 1400 Msun whereas the mass in the ridge is 15000 Msun. The accretion of these filaments onto the DR21 ridge, suggested by a previous molecular line study, could provide a continuous mass inflow to the ridge. In contrast to the striations seen in e.g., the Taurus region, these filaments are gravitationally unstable and form cores and protostars. These cores formed in the filaments potentially fall into the ridge. Both inflow and collisions of cores could be important to drive the observed high-mass star formation. The evolutionary gradient of star formation running from DR21 in the south to the northern branching is traced by decreasing dust temperature. This evolution and the ridge structure can be explained by two main filamentary components of the ridge that merged first in the south.Comment: 8 pages, 5 figures, accepted for publication as a Letter in Astronomy and Astrophysic

The vertebrate phylotypic stage and an early bilaterian-related stage in mouse embryogenesis defined by genomic information

BACKGROUND: Embryos of taxonomically different vertebrates are thought to pass through a stage in which they resemble one another morphologically. This "vertebrate phylotypic stage" may represent the basic vertebrate body plan that was established in the common ancestor of vertebrates. However, much controversy remains about when the phylotypic stage appears, and whether it even exists. To overcome the limitations of studies based on morphological comparison, we explored a comprehensive quantitative method for defining the constrained stage using expressed sequence tag (EST) data, gene ontologies (GO), and available genomes of various animals. If strong developmental constraints occur during the phylotypic stage of vertebrate embryos, then genes conserved among vertebrates would be highly expressed at this stage. RESULTS: We established a novel method for evaluating the ancestral nature of mouse embryonic stages that does not depend on comparative morphology. The numerical "ancestor index" revealed that the mouse indeed has a highly conserved embryonic period at embryonic day 8.0–8.5, the time of appearance of the pharyngeal arch and somites. During this period, the mouse prominently expresses GO-determined developmental genes shared among vertebrates. Similar analyses revealed the existence of a bilaterian-related period, during which GO-determined developmental genes shared among bilaterians are markedly expressed at the cleavage-to-gastrulation period. The genes associated with the phylotypic stage identified by our method are essential in embryogenesis. CONCLUSION: Our results demonstrate that the mid-embryonic stage of the mouse is indeed highly constrained, supporting the existence of the phylotypic stage. Furthermore, this candidate stage is preceded by a putative bilaterian ancestor-related period. These results not only support the developmental hourglass model, but also highlight the hierarchical aspect of embryogenesis proposed by von Baer. Identification of conserved stages and tissues by this method in various animals would be a powerful tool to examine the phylotypic stage hypothesis, and to understand which kinds of developmental events and gene sets are evolutionarily constrained and how they limit the possible variations of animal basic body plans

Determinants of cardiac troponin T elevation in COPD exacerbation – a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Cardiac Troponin T (cTnT) elevation during exacerbations of chronic obstructive pulmonary disease (COPD) is associated with increased mortality the first year after hospital discharge. The factors associated with cTnT elevation in COPD are not known.</p> <p>Methods</p> <p>From our hospital's database, all patients admitted with COPD exacerbation in 2000–03 were identified. 441 had measurement of cTnT performed. Levels of cTnT ≥ 0.04 μg/l were considered elevated. Clinical and historical data were retrieved from patient records, hospital and laboratory databases. Odds ratios for cTnT elevation were calculated using logistic regression.</p> <p>Results</p> <p>120 patients (27%) had elevated cTnT levels. The covariates independently associated with elevated cTnT were increasing neutrophil count, creatinine concentration, heart rate and Cardiac Infarction Injury Score (CIIS), and decreasing hemoglobin concentration. The adjusted odds ratios (95% confidence intervals in parentheses) for cTnT elevation were 1.52 (1.20–1.94) for a 5 × 10⁶/ml increase in neutrophils, 1.21 (1.12–1.32) for a 10 μmol/l increase in creatinine, 0.80 (0.69–0.92) for a 1 mg/dl increase in hemoglobin, 1.24 (1.09–1.42) for a 10 beats/minute increase in heart rate and 1.44 (1.15–1.82) for a 10 point increase in CIIS.</p> <p>Conclusion</p> <p>Multiple factors are associated with cTnT elevation, probably reflecting the wide panorama of comorbid conditions typically seen in COPD. The positive association between neutrophils and cTnT elevation is compatible with the concept that an exaggerated inflammatory response in COPD exacerbation may predispose for myocardial injury.</p