Developing and applying heterogeneous phylogenetic models with XRate

Modeling sequence evolution on phylogenetic trees is a useful technique in computational biology. Especially powerful are models which take account of the heterogeneous nature of sequence evolution according to the "grammar" of the encoded gene features. However, beyond a modest level of model complexity, manual coding of models becomes prohibitively labor-intensive. We demonstrate, via a set of case studies, the new built-in model-prototyping capabilities of XRate (macros and Scheme extensions). These features allow rapid implementation of phylogenetic models which would have previously been far more labor-intensive. XRate's new capabilities for lineage-specific models, ancestral sequence reconstruction, and improved annotation output are also discussed. XRate's flexible model-specification capabilities and computational efficiency make it well-suited to developing and prototyping phylogenetic grammar models. XRate is available as part of the DART software package: http://biowiki.org/DART .Comment: 34 pages, 3 figures, glossary of XRate model terminolog

Annually resolved North Atlantic marine climate over the last millennium

This is the final version of the article. Available from Nature Publishing Group via the DOI in this record.Owing to the lack of absolutely dated oceanographic information before the modern instrumental period, there is currently significant debate as to the role played by North Atlantic Ocean dynamics in previous climate transitions (for example, Medieval Climate Anomaly-Little Ice Age, MCA-LIA). Here we present analyses of a millennial-length, annually resolved and absolutely dated marine δ(18)O archive. We interpret our record of oxygen isotope ratios from the shells of the long-lived marine bivalve Arctica islandica (δ(18)O-shell), from the North Icelandic shelf, in relation to seawater density variability and demonstrate that solar and volcanic forcing coupled with ocean circulation dynamics are key drivers of climate variability over the last millennium. During the pre-industrial period (AD 1000-1800) variability in the sub-polar North Atlantic leads changes in Northern Hemisphere surface air temperatures at multi-decadal timescales, indicating that North Atlantic Ocean dynamics played an active role in modulating the response of the atmosphere to solar and volcanic forcing.We thank the members of the RV Bjarni Sæmundsson (Cruise No. B05-2006). This work was supported by the NERC-funded ULTRA project (Grant Number NE/H023356/1), NERC-funded CLAM project; (Project No. NE/N001176/1) and EU Millennium Project (Project number 017008). This study is a contribution to the Climate Change Consortium for Wales (C3W). We thank Brian Long (Bangor University) and Dr Julia Becker (Cardiff University) for their technical support, and Dr Manfred Mudelsee for his assistance with the trend analysis. We thank Dr Jessica Tierney and an anonymous reviewer for providing the constructive comments in the reviewing process

Comparative analysis of six common foraminiferal species of the genera Cassidulina, Paracassidulina, and Islandiella from the Arctic–North Atlantic domain

Morphologically similar benthic foraminiferal taxa can be difficult to separate. Aside from causing issues in taxonomy, incorrect identifications complicate our understanding of species-specific ecological preferences and result in flawed palaeoenvironmental reconstructions and geochemical results. Over the years, a number of studies have grouped together several key Arctic–North Atlantic species in various combinations, despite their distinct environmental preferences and/or stratigraphical differences, causing great confusion in the literature. These species include Cassidulina laevigata, Cassidulina neoteretis, Cassidulina teretis, Paracassidulina neocarinata, Islandiella helenae, and Islandiella norcrossi. Here, we provide for the first time a detailed comparison of these taxa. We present a compilation of the original species descriptions, along with clear, illustrated guidelines on how to separate these taxa to circumvent taxonomic confusion. We acknowledge that some features cannot easily be seen with a standard low-powered microscope, especially if specimens are not well preserved. In those cases, we recommend the following actions: (i) always strive to make a precise identification and at least differentiate between the three genera; (ii) where C. neoteretis and C. teretis cannot be separated, and where the stratigraphical context does not make the species identification obvious, specimens belonging to these taxa should be reported as C. teretis/C. neoteretis; and (iii) where specimens in a sample cannot be confidently assigned to a specific species of Islandiella or Cassidulina, specimens should be grouped as Islandiella spp. or Cassidulina spp., followed by naming the most dominant species in brackets. The improved identification of Cassidulina, Paracassidulina, and Islandiella specimens will ensure development of a better understanding of the ecological affinities of these key Arctic–North Atlantic taxa, consequently resulting in more accurate palaeoenvironmental reconstructions and geochemical data

Using Human Disease Outbreaks as a Guide to Multilevel Ecosystem Interventions

Human health often depends on environmental variables and is generally subject to widespread and comprehensive surveillance. Compared with other available measures of ecosystem health, human disease incidence may be one of the most useful and practical bioindicators for the often elusive gauge of ecologic well-being. We argue that many subtle ecosystem disruptions are often identified only as a result of detailed epidemiologic investigations after an anomalous increase in human disease incidence detected by routine surveillance mechanisms. Incidence rates for vector-mediated diseases (e.g., arboviral illnesses) and direct zoonoses (e.g., hantaviruses) are particularly appropriate as bioindicators to identify underlying ecosystem disturbances. Outbreak data not only have the potential to act as a pivotal warning system for ecosystem disruption, but may also be used to identify interventions for the preservation of ecologic health. With this approach, appropriate ecologically based strategies for remediation can be introduced at an earlier stage than would be possible based solely on environmental monitoring, thereby reducing the level of “ecosystem distress” as well as resultant disease burden in humans. This concept is discussed using local, regional, and global examples, thereby introducing the concept of multilevel ecosystem interventions

Thyroid Function and Body Weight: A Community-Based Longitudinal Study

OBJECTIVE: Body weight and overt thyroid dysfunction are associated. Cross-sectional population-based studies have repeatedly found that thyroid hormone levels, even within the normal reference range, might be associated with body weight. However, for longitudinal data, the association is less clear. Thus, we tested the association between serum thyrotropin (TSH) and body weight in a community-based sample of adult persons followed for 11 years. METHODS: A random sample of 4,649 persons aged 18-65 years from a general population participated in the DanThyr study in 1997-8. We included 2,102 individuals who participated at 11-year follow-up, without current or former treatment for thyroid disease and with measurements of TSH and weight at both examinations. Multiple linear regression models were used, stratified by sex and adjusted for age, smoking status, and leisure time physical activity. RESULTS: Baseline TSH concentration was not associated with change in weight (women, P = 0.17; men, P = 0.72), and baseline body mass index (BMI) was not associated with change in TSH (women, P = 0.21; men, P = 0.85). Change in serum TSH and change in weight were significantly associated in both sexes. Weight increased by 0.3 kg (95% confidence interval [CI] 0.1, 0.4, P = 0.005) in women and 0.8 kg (95% CI 0.1, 1.4, P = 0.02) in men for every one unit TSH (mU/L) increase. CONCLUSIONS: TSH levels were not a determinant of future weight changes, and BMI was not a determinant for TSH changes, but an association between weight change and TSH change was present

Efficacy of c-Met inhibitor for advanced prostate cancer

<p>Abstract</p> <p>Background</p> <p>Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer.</p> <p>Methods</p> <p>We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression.</p> <p>Results</p> <p>We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration.</p> <p>Conclusions</p> <p>The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer.</p

Prevalence and associated factors in burnout and psychological morbidity among substance misuse professionals

<p>Abstract</p> <p>Background</p> <p>Studies of psychological stress among substance misuse professionals rarely describe the nature of burnout and psychological morbidity. The main aim of this study was to determine the extent, pattern and predictors of psychological morbidity and burnout among substance misuse professionals.</p> <p>Methods</p> <p>This study was a cross-sectional mail survey of 194 clinical staff of substance misuse services in the former South Thames region of England, using the General Health Questionnaire (GHQ-12) the Maslach Burnout Inventory (MBI) as measures of psychological morbidity and burnout, respectively.</p> <p>Results</p> <p>Rates of psychological morbidity (82%: 95% CI = 76–87) and burnout (high emotional exhaustion – 33% [27–40]; high depersonalisation – 17% [12–23]; and diminished personal accomplishment – 36% [29–43]) were relatively high in the study sample. High levels of alienation and tension (job stressors) predicted emotional exhaustion and depersonalisation (burnout) but not psychological morbidity. Diminished personal accomplishment was associated with higher levels of psychological morbidity</p> <p>Conclusion</p> <p>In the sample of substance misuse professionals studied, rates of psychological morbidity and burnout were high, suggesting a higher level of vulnerability than in other health professionals. Furthermore, pathways to psychological morbidity and burnout are partially related. Therefore, targeted response is required to manage stress, burnout and psychological morbidity among substance misuse professionals. Such a response should be integral to workforce development.</p

Fractal assembly of micrometre-scale DNA origami arrays with arbitrary patterns

Self-assembled DNA nanostructures enable nanometre-precise patterning that can be used to create programmable molecular machines and arrays of functional materials. DNA origami is particularly versatile in this context because each DNA strand in the origami nanostructure occupies a unique position and can serve as a uniquely addressable pixel. However, the scale of such structures has been limited to about 0.05 square micrometres, hindering applications that demand a larger layout and integration with more conventional patterning methods. Hierarchical multistage assembly of simple sets of tiles can in principle overcome this limitation, but so far has not been sufficiently robust to enable successful implementation of larger structures using DNA origami tiles. Here we show that by using simple local assembly rules that are modified and applied recursively throughout a hierarchical, multistage assembly process, a small and constant set of unique DNA strands can be used to create DNA origami arrays of increasing size and with arbitrary patterns. We illustrate this method, which we term ‘fractal assembly’, by producing DNA origami arrays with sizes of up to 0.5 square micrometres and with up to 8,704 pixels, allowing us to render images such as the Mona Lisa and a rooster. We find that self-assembly of the tiles into arrays is unaffected by changes in surface patterns on the tiles, and that the yield of the fractal assembly process corresponds to about 0.95^(m − 1) for arrays containing m tiles. When used in conjunction with a software tool that we developed that converts an arbitrary pattern into DNA sequences and experimental protocols, our assembly method is readily accessible and will facilitate the construction of sophisticated materials and devices with sizes similar to that of a bacterium using DNA nanostructures

Curriculum Making as the Enactment of Dwelling in Places

This article uses an account of dwelling to interrogate the concept of curriculum making. Tim Ingold's use of dwelling to understand culture is productive here because of his implicit and explicit interest in intergenerational learning. His account of dwelling rests on a foundational ontological claim-that mental construction and representation are not the basis upon which we live in the world-which is very challenging for the kinds of curriculum making with which many educators are now familiar. It undermines assumptions of propositional knowledge and of the use of mental schemas to communicate and share. At the level of critique, then, dwelling destabilizes contemporary ideas of curriculum as textual, pre-specified content for transmission or pre-defined objectives or standardized activity. The positive claims of dwelling are equally challenging, for these are that the world is a domain of relational entanglement in which an organism can be no more than a point of growth for an emergent &lsquo;environment', and meaning only inheres in these relations. The paper articulates how differentiation (of learner, salient meanings, knowledge, skill and place) are possible in such an ontology, and how curriculum making can be understood from this perspective as being the remaking of relationships between these

Microbiology of the phyllosphere: a playground for testing ecological concepts

Many concepts and theories in ecology are highly debated, because it is often difficult to design decisive tests with sufficient replicates. Examples include biodiversity theories, succession concepts, invasion theories, coexistence theories, and concepts of life history strategies. Microbiological tests of ecological concepts are rapidly accumulating, but have yet to tap into their full potential to complement traditional macroecological theories. Taking the example of microbial communities on leaf surfaces (i.e. the phyllosphere), we show that most explorations of ecological concepts in this field of microbiology focus on autecology and population ecology, while community ecology remains understudied. Notable exceptions are first tests of the island biogeography theory and of biodiversity theories. Here, the phyllosphere provides the unique opportunity to set up replicated experiments, potentially moving fields such as biogeography, macroecology, and landscape ecology beyond theoretical and observational evidence. Future approaches should take advantage of the great range of spatial scales offered by the leaf surface by iteratively linking laboratory experiments with spatial simulation models