Showing papers by "University of St Andrews published in 2010"

Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation

Abstract: Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ∼7% of human malignancies and ∼60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.

Distance software: design and analysis of distance sampling surveys for estimating population size.

Abstract: Summary 1. Distance sampling is a widely used technique for estimating the size or density of biological populations. Many distance sampling designs and most analyses use the software Distance. 2. We briefly review distance sampling and its assumptions, outline the history, structure and capabilities of Distance, and provide hints on its use. 3. Good survey design is a crucial prerequisite for obtaining reliable results. Distance has a survey design engine, with a built-in geographic information system, that allows properties of different proposed designs to be examined via simulation, and survey plans to be generated. 4. A first step in analysis of distance sampling data is modelling the probability of detection. Distance contains three increasingly sophisticated analysis engines for this: conventional distance sampling, which models detection probability as a function of distance from the transect and assumes all objects at zero distance are detected; multiple-covariate distance sampling, which allows covariates in addition to distance; and mark–recapture distance sampling, which relaxes the assumption of certain detection at zero distance. 5. All three engines allow estimation of density or abundance, stratified if required, with associated measures of precision calculated either analytically or via the bootstrap. 6. Advanced analysis topics covered include the use of multipliers to allow analysis of indirect surveys (such as dung or nest surveys), the density surface modelling analysis engine for spatial and habitat modelling, and information about accessing the analysis engines directly from other software. 7.Synthesis and applications. Distance sampling is a key method for producing abundance and density estimates in challenging field conditions. The theory underlying the methods continues to expand to cope with realistic estimation situations. In step with theoretical developments, state-of-the-art software that implements these methods is described that makes the methods accessible to practising ecologists.

Genome Sequence of the Pea Aphid Acyrthosiphon pisum

Abstract: Aphids are important agricultural pests and also biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and the developmental causes of extreme phenotypic plasticity. Here we present the 464 Mb draft genome assembly of the pea aphid Acyrthosiphon pisum. This first published whole genome sequence of a basal hemimetabolous insect provides an outgroup to the multiple published genomes of holometabolous insects. Pea aphids are host-plant specialists, they can reproduce both sexually and asexually, and they have coevolved with an obligate bacterial symbiont. Here we highlight findings from whole genome analysis that may be related to these unusual biological features. These findings include discovery of extensive gene duplication in more than 2000 gene families as well as loss of evolutionarily conserved genes. Gene family expansions relative to other published genomes include genes involved in chromatin modification, miRNA synthesis, and sugar transport. Gene losses include genes central to the IMD immune pathway, selenoprotein utilization, purine salvage, and the entire urea cycle. The pea aphid genome reveals that only a limited number of genes have been acquired from bacteria; thus the reduced gene count of Buchnera does not reflect gene transfer to the host genome. The inventory of metabolic genes in the pea aphid genome suggests that there is extensive metabolite exchange between the aphid and Buchnera, including sharing of amino acid biosynthesis between the aphid and Buchnera. The pea aphid genome provides a foundation for post-genomic studies of fundamental biological questions and applied agricultural problems.

What is social learning

Abstract: Social learning is increasingly becoming a normative goal in natural resource management and policy. However, there remains little consensus over its meaning or theoretical basis. There are still considerable differences in understanding of the concept in the literature, including a number of articles published in Ecology & Society. Social learning is often conflated with other concepts such as participation and proenvironmental behavior, and there is often little distinction made between individual and wider social learning. Many unsubstantiated claims for social learning exist, and there is frequently confusion between the concept itself and its potential outcomes. This lack of conceptual clarity has limited our capacity to assess whether social learning has occurred, and if so, what kind of learning has taken place, to what extent, between whom, when, and how. This response attempts to provide greater clarity on the conceptual basis for social learning. We argue that to be considered social learning, a process must: (1) demonstrate that a change in understanding has taken place in the individuals involved; (2) demonstrate that this change goes beyond the individual and becomes situated within wider social units or communities of practice; and (3) occur through social interactions and processes between actors within a social network. A clearer picture of what we mean by social learning could enhance our ability to critically evaluate outcomes and better understand the processes through which social learning occurs. In this way, it may be possible to better facilitate the desired outcomes of social learning processes.

Antibacterial free fatty acids: activities, mechanisms of action and biotechnological potential

Abstract: Amongst the diverse and potent biological activities of free fatty acids (FFAs) is the ability to kill or inhibit the growth of bacteria. The antibacterial properties of FFAs are used by many organisms to defend against parasitic or pathogenic bacteria. Whilst their antibacterial mode of action is still poorly understood, the prime target of FFA action is the cell membrane, where FFAs disrupt the electron transport chain and oxidative phosphorylation. Besides interfering with cellular energy production, FFA action may also result from the inhibition of enzyme activity, impairment of nutrient uptake, generation of peroxidation and auto-oxidation degradation products or direct lysis of bacterial cells. Their broad spectrum of activity, non-specific mode of action and safety makes them attractive as antibacterial agents for various applications in medicine, agriculture and food preservation, especially where the use of conventional antibiotics is undesirable or prohibited. Moreover, the evolution of inducible FFA-resistant phenotypes is less problematic than with conventional antibiotics. The potential for commercial or biomedical exploitation of antibacterial FFAs, especially for those from natural sources, is discussed.

BioMOFs: metal-organic frameworks for biological and medical applications.

Abstract: The class of highly porous materials called metal-organic frameworks offer many opportunities for applications across biology and medicine. Their wide range of chemical composition makes toxicologically acceptable formulation possible, and their high level of functionality enables possible applications as imaging agents and as delivery vehicles for therapeutic agents. The challenges in the area encompass not only the development of new solids but also improvements in the formulation and processing of the materials, including tailoring the morphology and surface chemistry of the frameworks to fit the proposed applications.

Is accounting for sustainability actually accounting for sustainability…and how would we know? An exploration of narratives of organisations and the planet

Abstract: The emergence of sustainable development as the complex notion through which social and environmental issues must be addressed – whether at policy, personal or organisational levels – has had a growing influence in the accounting literature. In addition to explorations of what sustainability may mean for accounting and finance, we have experienced a growth in both critiques of sustainability reporting (sic) and in experiments and speculations on how accounting for sustainability might advance. This growth – as with social and environmental accounting before it – has very properly attracted critique. One convergent theme in that critique has been a challenge that much of the realist and procedural baggage associated with conventional accounting is no longer apposite when seeking to account for sustainability. What may be required, is a more nuanced understanding of what ‘sustainability’ actually is and how, if at all, it can have any empirical meaning at the level of the organisation. This essay seeks to initiate an auto-critique of accounting for sustainability via an examination of meanings and contradictions in sustainable development which, in turn, leads towards a suggestion for the development of multiple and conditional narratives that whilst no longer realist or totalising, explicitly challenge the hegemonic claims of business movements in the arena of sustainability and sustainable development.

Functional and evolutionary insights from the genomes of three parasitoid Nasonia species.

Abstract: We report here genome sequences and comparative analyses of three closely related parasitoid wasps: Nasonia vitripennis, N. giraulti, and N. longicornis. Parasitoids are important regulators of arthropod populations, including major agricultural pests and disease vectors, and Nasonia is an emerging genetic model, particularly for evolutionary and developmental genetics. Key findings include the identification of a functional DNA methylation tool kit; hymenopteran-specific genes including diverse venoms; lateral gene transfers among Pox viruses, Wolbachia, and Nasonia; and the rapid evolution of genes involved in nuclear-mitochondrial interactions that are implicated in speciation. Newly developed genome resources advance Nasonia for genetic research, accelerate mapping and cloning of quantitative trait loci, and will ultimately provide tools and knowledge for further increasing the utility of parasitoids as pest insect-control agents.

Long-term datasets in biodiversity research and monitoring: assessing change in ecological communities through time

Abstract: The growing need for baseline data against which efforts to reduce the rate of biodiversity loss can be judged highlights the importance of long-term datasets, some of which are as old as ecology itself. We review methods of evaluating change in biodiversity at the community level using these datasets, and contrast whole-community approaches with those that combine information from different species and habitats. As all communities experience temporal turnover, one of the biggest challenges is distinguishing change that can be attributed to external factors, such as anthropogenic activities, from underlying natural change. We also discuss methodological issues, such as false alerts and modifications in design, of which users of these data sets need to be aware.

How culture shaped the human genome: bringing genetics and the human sciences together

Abstract: Researchers from diverse backgrounds are converging on the view that human evolution has been shaped by gene-culture interactions. Theoretical biologists have used population genetic models to demonstrate that cultural processes can have a profound effect on human evolution, and anthropologists are investigating cultural practices that modify current selection. These findings are supported by recent analyses of human genetic variation, which reveal that hundreds of genes have been subject to recent positive selection, often in response to human activities. Here, we collate these data, highlighting the considerable potential for cross-disciplinary exchange to provide novel insights into how culture has shaped the human genome.

The New Psychology of Leadership: Identity, Influence and Power

Abstract: According to John Adair, the most important word in the leader's vocabulary is "we" and the least important word is "I". But if this is true, it raises one important question: why do psychological analyses of leadership always focus on the leader as an individual - as the great "I"? One answer is that theorists and practitioners have never properly understood the psychology of "we-ness". This book fills this gap by presenting a new psychology of leadership that is the result of two decades of research inspired by social identity and self-categorization theories. The book argues that to succeed, leaders need to create, champion, and embed a group identity in order to cultivate an understanding of 'us' of which they themselves are representative. It also shows how, by doing this, they can make a material difference to the groups, organizations, and societies that they lead. Written in an accessible and engaging style, the book examines a range of central theoretical and practical issues, including the nature of group identity, the basis of authority and legitimacy, the dynamics of justice and fairness, the determinants of followership and charisma, and the practice and politics of leadership. The book will appeal to academics, practitioners and students in social and organizational psychology, sociology, political science and anyone interested in leadership, influence and power.

Physics of Solar Prominences: II—Magnetic Structure and Dynamics

Abstract: Observations and models of solar prominences are reviewed. We focus on non-eruptive prominences, and describe recent progress in four areas of prominence research: (1) magnetic structure deduced from observations and models, (2) the dynamics of prominence plasmas (formation and flows), (3) Magneto-hydrodynamic (MHD) waves in prominences and (4) the formation and large-scale patterns of the filament channels in which prominences are located. Finally, several outstanding issues in prominence research are discussed, along with observations and models required to resolve them.

The generation and evolution of the continental crust

Abstract: The continental crust is the archive of the geological history of the Earth. Only 7% of the crust is older than 2.5 Ga, and yet significantly more crust was generated before 2.5 Ga than subsequently. Zircons offer robust records of the magmatic and crust-forming events preserved in the continental crust. They yield marked peaks of ages of crystallization and of crust formation. The latter might reflect periods of high rates of crust generation, and as such be due to magmatism associated with deep-seated mantle plumes. Alternatively the peaks are artefacts of preservation, they mark the times of supercontinent formation, and magmas generated in some tectonic settings may be preferentially preserved. There is increasing evidence that depletion of the upper mantle was in response to early planetary differentiation events. Arguments in favour of large volumes of continental crust before the end of the Archaean, and the thickness of felsic and mafic crust, therefore rely on thermal models for the progressively cooling Earth. They are consistent with recent estimates that the rates of crust generation and destruction along modern subduction zones are strikingly similar. The implication is that the present volume of continental crust was established 2–3 Ga ago.

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

Abstract: The glycerophospholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE) account for greater than 50% of the total phospholipid species in eukaryotic membranes and thus play major roles in the structure and function of those membranes. In most eukaryotic cells, PC and PE are synthesized by an aminoalcoholphosphotransferase reaction, which uses sn-1,2-diradylglycerol and either CDP-choline or CDP-ethanolamine, respectively. This is the last step in a biosynthetic pathway known as the Kennedy pathway, so named after Eugene Kennedy who elucidated it over 50 years ago. This review will cover various aspects of the Kennedy pathway including: each of the biosynthetic steps, the functions and roles of the phospholipid products PC and PE, and how the Kennedy pathway has the potential of being a chemotherapeutic target against cancer and various infectious diseases.

Lithium Diffusion in Graphitic Carbon

Abstract: Graphiticcarboniscurrentlyconsideredthestate-of-the-artmaterial for the negative electrode in lithium ion cells, mainly due to its high reversibility and low operating potential. However, carbon anodes exhibit mediocre charge/ discharge rate performance, which contributes to severe transport-induced sur- face structural damage upon prolonged cycling and limits the lifetime of the cell. Lithium bulkdiffusion in graphitic carbon is not yet completely understood, partly due to the complexity of measuring bulk transport properties in finite-sized nonisotropic particles. To solvethis problem forgraphite, weuse the Devanathan- Stachurski electrochemical methodology combined with ab initio computations to deconvolute and quantify the mechanism of lithium ion diffusion in highly oriented pyrolytic graphite (HOPG). The results reveal inherent high lithium ion diffusivityinthedirectionparalleltothegrapheneplane(∼10 -7 -10 -6 cm 2 s -1 ),as comparedtosluggishlithiumiontransportalonggrainboundaries(∼10 -11 cm 2 s -1 ), indicating the possibility of rational design of carbonaceous materials and com- posite electrodes with very high rate capability. SECTION Energy Conversion and Storage

The Herschel ATLAS

Abstract: The Herschel ATLAS is the largest open-time key project that will be carried out on the Herschel Space Observatory. It will survey 570 deg2 of the extragalactic sky, 4 times larger than all the other Herschel extragalactic surveys combined, in five far-infrared and submillimeter bands. We describe the survey, the complementary multiwavelength data sets that will be combined with the Herschel data, and the six major science programs we are undertaking. Using new models based on a previous submillimeter survey of galaxies, we present predictions of the properties of the ATLAS sources in other wave bands.

A machine learning approach to predicting protein–ligand binding affinity with applications to molecular docking

Abstract: Motivation: Accurately predicting the binding affinities of large sets of diverse protein–ligand complexes is an extremely challenging task. The scoring functions that attempt such computational prediction are essential for analysing the outputs of molecular docking, which in turn is an important technique for drug discovery, chemical biology and structural biology. Each scoring function assumes a predetermined theory-inspired functional form for the relationship between the variables that characterize the complex, which also include parameters fitted to experimental or simulation data and its predicted binding affinity. The inherent problem of this rigid approach is that it leads to poor predictivity for those complexes that do not conform to the modelling assumptions. Moreover, resampling strategies, such as cross-validation or bootstrapping, are still not systematically used to guard against the overfitting of calibration data in parameter estimation for scoring functions. Results: We propose a novel scoring function (RF-Score) that circumvents the need for problematic modelling assumptions via non-parametric machine learning. In particular, Random Forest was used to implicitly capture binding effects that are hard to model explicitly. RF-Score is compared with the state of the art on the demanding PDBbind benchmark. Results show that RF-Score is a very competitive scoring function. Importantly, RF-Score's performance was shown to improve dramatically with training set size and hence the future availability of more high-quality structural and interaction data is expected to lead to improved versions of RF-Score. Contact:pedro.ballester@ebi.ac.uk; jbom@st-andrews.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Timing of India‐Asia collision: Geological, biostratigraphic, and palaeomagnetic constraints

Abstract: [1] A range of ages have been proposed for the timing of India-Asia collision; the range to some extent reflects different definitions of collision and methods used to date it. In this paper we discuss three approaches that have been used to constrain the time of collision: the time of cessation of marine facies, the time of the first arrival of Asian detritus on the Indian plate, and the determination of the relative positions of India and Asia through time. In the Qumiba sedimentary section located south of the Yarlung Tsangpo suture in Tibet, a previous work has dated marine facies at middle to late Eocene, by far the youngest marine sediments recorded in the region. By contrast, our biostratigraphic data indicate the youngest marine facies preserved at this locality are 50.6–52.8 Ma, in broad agreement with the timing of cessation of marine facies elsewhere throughout the region. Double dating of detrital zircons from this formation, by U-Pb and fission track methods, indicates an Asian contribution to the rocks thus documenting the time of arrival of Asian material onto the Indian plate at this time and hence constraining the time of India-Asia collision. Our reconstruction of the positions of India and Asia by using a compilation of published palaeomagnetic data indicates initial contact between the continents in the early Eocene. We conclude the paper with a discussion on the viability of a recent assertion that collision between India and Asia could not have occurred prior to ∼35 Ma.

Development of the Spatial Representation System in the Rat

Abstract: In the adult brain, space and orientation are represented by an elaborate hippocampal-parahippocampal circuit consisting of head-direction cells, place cells, and grid cells. We report that a rudimentary map of space is already present when 2½-week-old rat pups explore an open environment outside the nest for the first time. Head-direction cells in the pre- and parasubiculum have adultlike properties from the beginning. Place and grid cells are also present but evolve more gradually. Grid cells show the slowest development. The gradual refinement of the spatial representation is accompanied by an increase in network synchrony among entorhinal stellate cells. The presence of adultlike directional signals at the onset of navigation raises the possibility that such signals are instrumental in setting up networks for place and grid representation.

Why Copy Others? Insights from the Social Learning Strategies Tournament

Abstract: Social learning (learning through observation or interaction with other individuals) is widespread in nature and is central to the remarkable success of humanity, yet it remains unclear why copying is profitable and how to copy most effectively To address these questions, we organized a computer tournament in which entrants submitted strategies specifying how to use social learning and its asocial alternative (for example, trial-and-error learning) to acquire adaptive behavior in a complex environment Most current theory predicts the emergence of mixed strategies that rely on some combination of the two types of learning In the tournament, however, strategies that relied heavily on social learning were found to be remarkably successful, even when asocial information was no more costly than social information Social learning proved advantageous because individuals frequently demonstrated the highest-payoff behavior in their repertoire, inadvertently filtering information for copiers The winning strategy (discountmachine) relied nearly exclusively on social learning and weighted information according to the time since acquisition

Human Ovarian Reserve from Conception to the Menopause

Abstract: The human ovary contains a fixed number of non-growing follicles (NGFs) established before birth that decline with increasing age culminating in the menopause at 50-51 years. The objective of this study is to model the age-related population of NGFs in the human ovary from conception to menopause. Data were taken from eight separate quantitative histological studies (n = 325) in which NGF populations at known ages from seven weeks post conception to 51 years (median 32 years) were calculated. The data set was fitted to 20 peak function models, with the results ranked by obtained r2 correlation coefficient. The highest ranked model was chosen. Our model matches the log-adjusted NGF population from conception to menopause to a five-parameter asymmetric double Gaussian cumulative (ADC) curve (r2 = 0.81). When restricted to ages up to 25 years, the ADC curve has r2 = 0.95. We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. Furthermore, we found that the rate of NGF recruitment towards maturation for most women increases from birth until approximately age 14 years then decreases towards the menopause. To our knowledge, this is the first model of ovarian reserve from conception to menopause. This model allows us to estimate the number of NGFs present in the ovary at any given age, suggests that 81% of the variance in NGF populations is due to age alone, and shows for the first time, to our knowledge, that the rate of NGF recruitment increases from birth to age 14 years then declines with age until menopause. An increased understanding of the dynamics of human ovarian reserve will provide a more scientific basis for fertility counselling for both healthy women and those who have survived gonadotoxic cancer treatments.

THE CANADA-FRANCE HIGH-z QUASAR SURVEY: NINE NEW QUASARS AND THE LUMINOSITY FUNCTION AT REDSHIFT 6

Abstract: We present discovery imaging and spectroscopy for nine new z ∼ 6 quasars found in the Canada–France High-z Quasar Survey (CFHQS) bringing the total number of CFHQS quasars to 19. By combining the CFHQS with the more luminous Sloan Digital Sky Survey sample, we are able to derive the quasar luminosity function from a sample of 40 quasars at redshifts 5.74

Intra-unit-cell electronic nematicity of the high- T c copper-oxide pseudogap states

Abstract: In the high-transition-temperature (high-T(c)) superconductors the pseudogap phase becomes predominant when the density of doped holes is reduced. Within this phase it has been unclear which electronic symmetries (if any) are broken, what the identity of any associated order parameter might be, and which microscopic electronic degrees of freedom are active. Here we report the determination of a quantitative order parameter representing intra-unit-cell nematicity: the breaking of rotational symmetry by the electronic structure within each CuO(2) unit cell. We analyse spectroscopic-imaging scanning tunnelling microscope images of the intra-unit-cell states in underdoped Bi(2)Sr(2)CaCu(2)O(8 +) (delta) and, using two independent evaluation techniques, find evidence for electronic nematicity of the states close to the pseudogap energy. Moreover, we demonstrate directly that these phenomena arise from electronic differences at the two oxygen sites within each unit cell. If the characteristics of the pseudogap seen here and by other techniques all have the same microscopic origin, this phase involves weak magnetic states at the O sites that break 90 degrees -rotational symmetry within every CuO(2) unit cell.