Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system

BACKGROUND: Bile acids (BAs) regulate cells by activating nuclear and membrane-bound receptors. G protein coupled bile acid receptor 1 (GpBAR1) is a membrane-bound G-protein-coupled receptor that can mediate the rapid, transcription-independent actions of BAs. Although BAs have well-known actions on motility and secretion, nothing is known about the localization and function of GpBAR1 in the gastrointestinal tract. METHODS: We generated an antibody to the C-terminus of human GpBAR1, and characterized the antibody by immunofluorescence and Western blotting of HEK293-GpBAR1-GFP cells. We localized GpBAR1 immunoreactivity (IR) and mRNA in the mouse intestine, and determined the mechanism by which BAs activate GpBAR1 to regulate intestinal motility. KEY RESULTS: The GpBAR1 antibody specifically detected GpBAR1-GFP at the plasma membrane of HEK293 cells, and interacted with proteins corresponding in mass to the GpBAR1-GFP fusion protein. GpBAR1-IR and mRNA were detected in enteric ganglia of the mouse stomach and small and large intestine, and in the muscularis externa and mucosa of the small intestine. Within the myenteric plexus of the intestine, GpBAR1-IR was localized to approximately 50% of all neurons and to >80% of inhibitory motor neurons and descending interneurons expressing nitric oxide synthase. Deoxycholic acid, a GpBAR1 agonist, caused a rapid and sustained inhibition of spontaneous phasic activity of isolated segments of ileum and colon by a neurogenic, cholinergic and nitrergic mechanism, and delayed gastrointestinal transit. CONCLUSIONS & INFERENCES: G protein coupled bile acid receptor 1 is unexpectedly expressed in enteric neurons. Bile acids activate GpBAR1 on inhibitory motor neurons to release nitric oxide and suppress motility, revealing a novel mechanism for the actions of BAs on intestinal motility.

Evidence for global climate reorganization during medieval times

A synthesis of global climate model results and inferences from proxy records suggests an increased sea surface temperature gradient between the tropical Indian and Pacific Oceans during medieval times.

Was the Australian meat and livestock corporations advertising efficient?

A theory of the allocation of producer levies earmarked for downstream promotion is developed and applied to quarterly series (1970:2–1988:4) on red-meats advertising by the Australian Meat and Live-stock Corporation. Robust inferences about program efficiency are contained in the coefficients of changes in promotion effort regressed against movements in farm price and quantity. Empirical evidence of program efficiency is inconclusive. While the deeper issue of efficient disbursement of funds remains an open question, there is evidence, at least, of efficient taxation.

Entity-based semantic search on conversational transcripts semantic

This paper describes the implementation of a semantic web search engine on conversation styled transcripts. Our choice of data is Hansard, a publicly available conversation style transcript of parliamentary debates. The current search engine implementation on Hansard is limited to running search queries based on keywords or phrases hence lacks the ability to make semantic inferences from user queries. By making use of knowledge such as the relationship between members of parliament, constituencies, terms of office, as well as topics of debates the search results can be improved in terms of both relevance and coverage. Our contribution is not algorithmic instead we describe how we exploit a collection of external data sources, ontologies, semantic web vocabularies and named entity extraction in the analysis of underlying semantics of user queries as well as the semantic enrichment of the search index thereby improving the quality of results.

Stable isotope and modelling evidence for CO2 as a driver of glacial–interglacial vegetation shifts in southern Africa

Atmospheric CO2 concentration is hypothesized to influence vegetation distribution via tree–grass competition, with higher CO2 concentrations favouring trees. The stable carbon isotope (δ13C) signature of vegetation is influenced by the relative importance of C4 plants (including most tropical grasses) and C3 plants (including nearly all trees), and the degree of stomatal closure – a response to aridity – in C3 plants. Compound-specific δ13C analyses of leaf-wax biomarkers in sediment cores of an offshore South Atlantic transect are used here as a record of vegetation changes in subequatorial Africa. These data suggest a large increase in C3 relative to C4 plant dominance after the Last Glacial Maximum. Using a process-based biogeography model that explicitly simulates 13C discrimination, it is shown that precipitation and temperature changes cannot explain the observed shift in δ13C values. The physiological effect of increasing CO2 concentration is decisive, altering the C3/C4 balance and bringing the simulated and observed δ13C values into line. It is concluded that CO2 concentration itself was a key agent of vegetation change in tropical southern Africa during the last glacial–interglacial transition. Two additional inferences follow. First, long-term variations in terrestrial δ13Cvalues are not simply a proxy for regional rainfall, as has sometimes been assumed. Although precipitation and temperature changes have had major effects on vegetation in many regions of the world during the period between the Last Glacial Maximum and recent times, CO2 effects must also be taken into account, especially when reconstructing changes in climate between glacial and interglacial states. Second, rising CO2 concentration today is likely to be influencing tree–grass competition in a similar way, and thus contributing to the "woody thickening" observed in savannas worldwide. This second inference points to the importance of experiments to determine how vegetation composition in savannas is likely to be influenced by the continuing rise of CO2 concentration.

Using paleo-climate comparisons to constrain future projections in CMIP5

We present a description of the theoretical framework and "best practice" for using the paleo-climate model component of the Coupled Model Intercomparison Project (Phase 5) (CMIP5) to constrain future projections of climate using the same models. The constraints arise from measures of skill in hindcasting paleo-climate changes from the present over 3 periods: the Last Glacial Maximum (LGM) (21 thousand years before present, ka), the mid-Holocene (MH) (6 ka) and the Last Millennium (LM) (850–1850 CE). The skill measures may be used to validate robust patterns of climate change across scenarios or to distinguish between models that have differing outcomes in future scenarios. We find that the multi-model ensemble of paleo-simulations is adequate for addressing at least some of these issues. For example, selected benchmarks for the LGM and MH are correlated to the rank of future projections of precipitation/temperature or sea ice extent to indicate that models that produce the best agreement with paleoclimate information give demonstrably different future results than the rest of the models. We also find that some comparisons, for instance associated with model variability, are strongly dependent on uncertain forcing timeseries, or show time dependent behaviour, making direct inferences for the future problematic. Overall, we demonstrate that there is a strong potential for the paleo-climate simulations to help inform the future projections and urge all the modeling groups to complete this subset of the CMIP5 runs.

Combined neurostimulation and neuroimaging in cognitive neuroscience: past, present, and future

Modern neurostimulation approaches in humans provide controlled inputs into the operations of cortical regions, with highly specific behavioral consequences. This enables causal structure–function inferences, and in combination with neuroimaging, has provided novel insights into the basic mechanisms of action of neurostimulation on dis- tributed networks. For example,more recent work has established the capacity of transcranialmagnetic stimulation (TMS) to probe causal interregional influences, and their interaction with cognitive state changes. Combinations of neurostimulation and neuroimaging now face the challenge of integrating the known physiological effects of neu- rostimulationwith theoretical and biologicalmodels of cognition, for example,when theoretical stalemates between opposing cognitive theories need to be resolved. This will be driven by novel developments, including biologically informedcomputational network analyses for predicting the impactofneurostimulationonbrainnetworks, as well as novel neuroimaging and neurostimulation techniques. Such future developments may offer an expanded set of tools withwhich to investigate structure–function relationships, and to formulate and reconceptualize testable hypotheses about complex neural network interactions and their causal roles in cognition

L1 acquisition across Portuguese dialects: modular and interdisciplinary interfaces as sources of explanation

This study investigates the child (L1) acquisition of properties at the interfaces of morpho-syntax, syntax-semantics and syntax-pragmatics, by focusing on inflected infinitives in European Portuguese (EP). Three child groups were tested, 6–7-year-olds, 9–10-year-olds and 11–12-year-olds, as well as an adult control group. The data demonstrate that children as young as 6 have knowledge of the morpho-syntactic properties of inflected infinitives, although they seem at first glance to show partially insufficient knowledge of their syntax–semantic interface properties (i.e. non-obligatory control properties), differently from children aged 9 and older, who show clearer evidence of knowledge of both types of properties. However, in general, both morpho-syntactic and syntax–semantics interface properties are also accessible to 6–7-year-old children, although these children give preference to a range of interpretations partially different from the adults; in certain cases, they may not appeal to certain pragmatic inferences that permit additional interpretations to adults and older children. Crucially, our data demonstrate that EP children master the two types of properties of inflected infinitives years before Brazilian Portuguese children do (Pires and Rothman, 2009a and Pires and Rothman, 2009b), reasons for and implications of which we discuss in detail.

Automated identification and tracking of polar-cap plasma patches at solar minimum

A method of automatically identifying and tracking polar-cap plasma patches, utilising data inversion and feature-tracking methods, is presented. A well-established and widely used 4-D ionospheric imaging algorithm, the Multi-Instrument Data Assimilation System (MIDAS), inverts slant total electron content (TEC) data from ground-based Global Navigation Satellite System (GNSS) receivers to produce images of the free electron distribution in the polar-cap ionosphere. These are integrated to form vertical TEC maps. A flexible feature-tracking algorithm, TRACK, previously used extensively in meteorological storm-tracking studies is used to identify and track maxima in the resulting 2-D data fields. Various criteria are used to discriminate between genuine patches and "false-positive" maxima such as the continuously moving day-side maximum, which results from the Earth's rotation rather than plasma motion. Results for a 12-month period at solar minimum, when extensive validation data are available, are presented. The method identifies 71 separate structures consistent with patch motion during this time. The limitations of solar minimum and the consequent small number of patches make climatological inferences difficult, but the feasibility of the method for patches larger than approximately 500 km in scale is demonstrated and a larger study incorporating other parts of the solar cycle is warranted. Possible further optimisation of discrimination criteria, particularly regarding the definition of a patch in terms of its plasma concentration enhancement over the surrounding background, may improve results.

Linguistic relativity in SLA: towards a new research programme

The purpose of the current article is to support the investigation of linguistic relativity in second language acquisition and sketch methodological and theoretical prerequisites toward developing the domain into a full research program. We identify and discuss three theoretical-methodological components that we believe are needed to succeed in this enterprise. First, we highlight the importance of using nonverbal methods to study linguistic relativity effects in second language (L2) speakers. The use of nonverbal tasks is necessary in order to avoid the circularity that arises when inferences about nonverbal behavior are made on the basis of verbal evidence alone. Second, we identify and delineate the likely cognitive mechanisms underpinning cognitive restructuring in L2 speakers by introducing the theoretical framework of associative learning. By doing so, we demonstrate that the extent and nature of cognitive restructuring in L2 speakers is essentially a function of variation in individual learners’ trajectories. Third, we offer an in-depth discussion of the factors (e.g., L2 proficiency and L2 use) that characterize those trajectories, anchoring them to the framework of associative learning, and reinterpreting their relative strength in predicting L2 speaker cognition

Time to decide? Simplicity and congruity in comparative judgment

What is the relationship between magnitude judgments relying on directly available characteristics versus probabilistic cues? Question frame was manipulated in a comparative judgment task previously assumed to involve inference across a probabilistic mental model (e.g., “which city is largest” – the “larger” question – versus “which city is smallest” – the “smaller” question). Participants identified either the largest or smallest city (Experiments 1a, 2) or the richest or poorest person (Experiment 1b) in a three-alternative forced choice (3-AFC) task (Experiment 1) or 2-AFC task (Experiment 2). Response times revealed an interaction between question frame and the number of options recognized. When asked the smaller question, response times were shorter when none of the options were recognized. The opposite pattern was found when asked the larger question: response time was shorter when all options were recognized. These task-stimuli congruity results in judgment under uncertainty are consistent with, and predicted by, theories of magnitude comparison which make use of deductive inferences from declarative knowledge.

Effects of action observation on corticospinal excitability: muscle specificity, direction, and timing of the mirror response

Many human behaviours and pathologies have been attributed to the putative mirror neuron system, a neural system that is active during both the observation and execution of actions. While there are now a very large number of papers on the mirror neuron system, variations in the methods and analyses employed by researchers mean that the basic characteristics of the mirror response are not clear. This review focuses on three important aspects of the mirror response, as measured by modulations in corticospinal excitability: (1) muscle specificity, (2) direction, and (3) timing of modulation. We focus mainly on electromyographic (EMG) data gathered following single-pulse transcranial magnetic stimulation (TMS), because this method provides precise information regarding these three aspects of the response. Data from paired-pulse TMS paradigms and peripheral nerve stimulation (PNS) are also considered when we discuss the possible mechanisms underlying the mirror response. In this systematic review of the literature, we examine the findings of 85 TMS and PNS studies of the human mirror response, and consider the limitations and advantages of the different methodological approaches these have adopted in relation to discrepancies between their findings. We conclude by proposing a testable model of how action observation modulates corticospinal excitability in humans. Specifically, we propose that action observation elicits an early, non-specific facilitation of corticospinal excitability (at around 90 ms from action onset), followed by a later modulation of activity specific to the muscles involved in the observed action (from around 200 ms). Testing this model will greatly advance our understanding of the mirror mechanism and provide a more stable grounding on which to base inferences about its role in human behaviour.

Animal infectious disease and climate change: a selected review

It is indisputable that climate is an important factor in many livestock diseases. Nevertheless, our knowledge of the impact of climate change on livestock infectious diseases is much less certain. Therefore, the aim of the article is to conduct a systematic review of the literature on the topic utilizing available retrospective data and information. Across a corpus of 175 formal publications, limited empirical evidence was offered to underpin many of the main arguments. The literature reviewed was highly polarized and often inconsistent regarding what the future may hold. Historical explorations were rare. However, identifying past drivers to livestock disease may not fully capture the extent that new and unknown drivers will influence future change. As such, our current predictive capacity is low. We offer a number of recommendations to strengthen this capacity in the coming years. We conclude that our current approach to research on the topic is limiting and unlikely to yield sufficient, actionable evidence to inform future praxis. Therefore, we argue for the creation of a reflexive, knowledge-based system, underpinned by a collective intelligence framework to support the drawing of inferences across the literature.

An energy budget agent-based model of earthworm populations and its application to study the effects of pesticides

Earthworms are important organisms in soil communities and so are used as model organisms in environmental risk assessments of chemicals. However current risk assessments of soil invertebrates are based on short-term laboratory studies, of limited ecological relevance, supplemented if necessary by site-specific field trials, which sometimes are challenging to apply across the whole agricultural landscape. Here, we investigate whether population responses to environmental stressors and pesticide exposure can be accurately predicted by combining energy budget and agent-based models (ABMs), based on knowledge of how individuals respond to their local circumstances. A simple energy budget model was implemented within each earthworm Eisenia fetida in the ABM, based on a priori parameter estimates. From broadly accepted physiological principles, simple algorithms specify how energy acquisition and expenditure drive life cycle processes. Each individual allocates energy between maintenance, growth and/or reproduction under varying conditions of food density, soil temperature and soil moisture. When simulating published experiments, good model fits were obtained to experimental data on individual growth, reproduction and starvation. Using the energy budget model as a platform we developed methods to identify which of the physiological parameters in the energy budget model (rates of ingestion, maintenance, growth or reproduction) are primarily affected by pesticide applications, producing four hypotheses about how toxicity acts. We tested these hypotheses by comparing model outputs with published toxicity data on the effects of copper oxychloride and chlorpyrifos on E. fetida. Both growth and reproduction were directly affected in experiments in which sufficient food was provided, whilst maintenance was targeted under food limitation. Although we only incorporate toxic effects at the individual level we show how ABMs can readily extrapolate to larger scales by providing good model fits to field population data. The ability of the presented model to fit the available field and laboratory data for E. fetida demonstrates the promise of the agent-based approach in ecology, by showing how biological knowledge can be used to make ecological inferences. Further work is required to extend the approach to populations of more ecologically relevant species studied at the field scale. Such a model could help extrapolate from laboratory to field conditions and from one set of field conditions to another or from species to species.

Modeling the observed proton aurora and ionospheric convection responses to changes in the IMF clock angle: 2. Persistence of ionospheric convection

We apply a numerical model of time-dependent ionospheric convection to two directly driven reconnection pulses during a 15-min interval of southward IMF on 26 November 2000. The model requires an input magnetopause reconnection rate variation, which is here derived from the observed variation in the upstream IMF clock angle, q. The reconnection rate is mapped to an ionospheric merging gap, the MLT extent of which is inferred from the Doppler-shifted Lyman-a emission on newly opened field lines, as observed by the FUV instrument on the IMAGE spacecraft. The model is used to reproduce a variety of features observed during this event: SuperDARN observations of the ionospheric convection pattern and transpolar voltage; FUV observations of the growth of patches of newly opened flux; FUVand in situ observations of the location of the Open-Closed field line Boundary (OCB) and a cusp ion step. We adopt a clock angle dependence of the magnetopause reconnection electric field, mapped to the ionosphere, of the form Enosin4(q/2) and estimate the peak value, Eno, by matching observed and modeled variations of both the latitude, LOCB, of the dayside OCB (as inferred from the equatorward edge of cusp proton emissions seen by FUV) and the transpolar voltage FPC (as derived using the mapped potential technique from SuperDARN HF radar data). This analysis also yields the time constant tOCB with which the open-closed boundary relaxes back toward its equilibrium configuration. For the case studied here, we find tOCB = 9.7 ± 1.3 min, consistent with previous inferences from the observed response of ionospheric flow to southward turnings of the IMF. The analysis confirms quantitatively the concepts of ionospheric flow excitation on which the model is based and explains some otherwise anomalous features of the cusp precipitation morphology.