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During the last decades, the analytical techniques of X-ray absorption contrast imaging have systematically gained greater relevance, mainly due to the ability to attain non-destructive exploration the sample interior. The significant improvement in spatial resolution offered by X-ray micro-tomography, as compared to conventional computed tomography, has motivated its insertion in many biomedical fields, among which dentistry stands out. Particularly, for endodontics, microCT appears as a method of remarkable potential interest to study procedures involved in root canal treatments, where one of the main needs is the anatomical characterization of the root canal in the teeth. The present work reports on the adaptation of the micro CT equipment of the LIIFAMIRx⃝laboratory at the E. Gaviola Physics Institute, CONICET and UNC, thus allowing to acquire radiographic images of dental samples of interest, to be later used in the implementation of algorithms, intended to tomographic reconstruction and volume segmentation. As a result, radiographic images of premolar teeth were obtained with good contrast between the different materials present, and three-dimensional representations, whose visualization is comparable with the real samples. Moreover, it was possible to characterize the root canal volume of the tooth both in its natural form and after having undergone the instrumentation process in which the pulp tissue is extracted.

Abstract High spectral resolution infrared sounders are an integral component of the global observing system and are used in a broad range of applications. This is enabled by their high accuracies which are ensured by rigorous calibration/validation activities. One of these activities is the post‐launch intercomparison with other high spectral resolution infrared sounders using simultaneous nadir overpasses (SNOs). This paper introduces a novel application of the previously developed SNO methodology by including time difference histogram symmetrization and a spatial sampling uncertainty. Where possible, radiometric measurement uncertainties are included and propagated through the statistics. Comparisons of Atmospheric Infrared Sounder (AIRS), METOP‐A/B/C Infrared Atmospheric Sounding Interferometer (IASI), and Cross‐track Infrared Sounder (CrIS) from 1 October 2019, to 1 October 2020, are analyzed. Results show AIRS and IASI differences as well as CrIS and AIRS differences are generally less than 0.4 K across the spectrum, and CrIS and IASI differences are generally less than 0.25 K. Comparison of the Suomi National Polar‐Orbiting Partnership and NOAA‐20 CrIS instruments via IASI and AIRS shows differences are generally less than 0.1 K across all bands and that the two CrIS instruments statistically agree within their radiometric uncertainties except for the narrow 2,370 cm−1 region where artifacts due to brightness temperature conversion are prone to occur.

Abstract Background Aviation has used a real-time observation method to advance anonymised feedback to the front-line and improve safe practice. Using an experiential learning method, this pilot study aimed to develop an observation-based real-time learning tool for final-year medical students with potential wider use in clinical practice. Methods Using participatory action research, we collected data on medical students’ observations of real-time clinical practice. The observation data was analysed thematically and shared with a steering group of experts to agree a framework for recording observations. A sample of students (observers) and front-line clinical staff (observed) completed one-to-one interviews on their experiences. The interviews were analysed using thematic analysis. Results Thirty-seven medical students identified 917 issues in wards, theatres and clinics in an acute hospital trust. These issues were grouped into the themes of human influences, work environment and systems. Aviation approaches were adapted to develop an app capable of recording real-time positive and negative clinical incidents. Five students and eleven clinical staff were interviewed and shared their views on the value of a process that helped them learn and has the potential to advance the quality of practice. Concerns were shared about how the observational process is managed. Conclusion The study developed an app (Healthcare Team Observations for Patient Safety—HTOPS), for recording good and poor clinical individual and team behaviour in acute-care practice. The process advanced medical student learning about patient safety. The tool can identify the totality of patient safety practice and illuminate strength and weakness. HTOPS offers the opportunity for collective ownership of safety concerns without blame and has been positively received by all stakeholders. The next steps will further refine the app for use in all clinical areas for capturing light noise.

Mennerotodus Zhelezko, 1994, is an extinct lamniform shark known to occur in Paleogene strata of the Tethyan region of Asia and Europe. Although only a single species has been named, multiple subspecies have been erected and used as biostratigraphic tools in Asia. The genus has not been reported with confidence outside of the Tethyan region, but we have identified two new species of Mennerotodus from Paleogene deposits of the southeastern United States. Mennerotodus mackayi sp. nov. is described by teeth occurring in the lower Paleocene (Danian Stage) Pine Barren Member of the Clayton Formation of southern Alabama. A middle Eocene (Bartonian) species, Mennerotodus parmleyi sp. nov., is based on material occurring in the Clinchfield Formation in central Georgia. The early Paleocene record could indicate a North American origin for Mennerotodus relatively soon after the K–Pg event, with subsequent radiation to other parts of the world. The genus is likely more widely distributed than is currently known, but teeth can easily be overlooked due to their similarity to other taxa.

Background Vascular surgery has one of the highest unplanned 30‐day readmission rates of all surgical specialties. The degree to which these may be avoidable and the optimal strategies to reduce their occurrence are unknown. The aim of this study was to identify and classify avoidable 30‐day readmissions in patients undergoing vascular surgery in order to plan targeted interventions to reduce their occurrence, improve outcomes and reduce cost. Methods A retrospective analysis of discharges over a 12‐month period from a single tertiary vascular unit was performed. A multidisciplinary panel conducted a manual case‐note review to identify and classify those 30‐day unplanned emergency readmissions deemed avoidable. Results An unplanned 30‐day readmission occurred in 72 of 885 admissions (8·1 per cent). These unplanned readmissions were deemed avoidable in 36 (50 per cent) of these 72 patients, and were most frequently due to unresolved medical issues (19 of 36, 53 per cent) and inappropriate admission with the potential for outpatient management (7 of 36, 19 per cent). A smaller number were due to inadequate social care provision (4 of 36, 11 per cent) and the occurrence of other avoidable adverse events (4 of 36, 11 per cent). Conclusion Half of all 30‐day readmissions following vascular surgery are potentially avoidable. Multidisciplinary coordination of inpatient care and the transition from hospital to community care after discharge need to be improved.

A lack of knowledge about rabbit herbage intake during grazing limits the development of organic rabbit production. This study describes rabbit herbage intake under a wide range of grazing conditions and characterises the factors that decrease rabbit herbage intake and daily weight gain. It was conducted with growing rabbits reared in moving cages with 0.4 m2 of grazing area per rabbit. Rabbits grazed on pastures dominated by legumes (LEG) or grass and forbs (GRF) and received 60 g/day per rabbit of a complete pelleted feed. Three trials were performed in winter, summer and spring. Mean herbage allowance was 27% higher in LEG (62.3 g dry matter (DM)/kg metabolic weight (MW), equal to kg0.75) than in GRF (49.2 g DM/kg MW). Herbage intake varied greatly (36.3±18.0 g DM/kg MW) among trials and was higher in LEG than in GRF (39.5v.34.1 g DM/kg MW). For both pasture types, herbage intake was logarithmically related to herbage allowance and plateaued around 75 g DM/kg MW. Crude protein and digestible energy (DE) intake differed by pasture type and season. Mean CP intake was 40% higher in LEG (15.0 g/kg MW) than in GRF (10.7 g/kg MW). In summer, mean DE intake was 27% higher in LEG than in GRF but no significant differences in DE intake were found between LEG and GRF in winter and spring. Maximum DE intake plateaued near 1000 kJ/kg MW. Daily weight gain was always higher for rabbits grazing LEG (mean=22.6 g) than GRF (mean=16.0 g). Weight gain was significantly related to CP intake, whereas DE intake had no significant effect. Meeting the objective of mean daily weight gain of 20 g requires herbage intake of 32 and 50 g DM/kg MW in LEG and GRF, respectively. Therefore, according to the herbage use efficiency observed in our experiments, herbage allowance must reach 42 and 78 g DM/kg MW in LEG and GRF, respectively. When herbage allowance is lower, rabbits cannot meet the CP intake (13 g/kg MW) required for this weight gain objective.

Following the publication of this article [1], the authors reported a number of errors which are given below.

Intensification and diversification of human-induced pressures in marine ecosystems have raised concerns over several sustainability-diminishing consequences, such as hypoxia and overexploitation of resources. We present the PlanWise4Blue tool (PW4B), which assesses the cumulative effects of multiple pressures on nature assets. In order to express the sensitivity of different nature assets to a plethora of pressure combinations, a meta-analysis based on published literature and available datasets was performed to calculate a set of standardized effect sizes. These calculations relied mostly on experimental or observational evidence; expert knowledge was used to estimate the impact coefficients only in the absence of impact data. Spatial modelling techniques (machine learning) were used to model the probability of occurrence and abundances of different nature assets in lattice grids with a cell size of 1 km2. Users can use the portal to estimate impacted areas and changes to natural assets caused by any combination of anthropogenic pressure. The PW4B tool can be used to predict individual and synergistic effects — both current and future — of a wide range of human activities and can be used regardless of scientific background. The tool was tested in the Baltic Sea region in coordination with the process of the Estonian Maritime Spatial Planning. This test evaluated the combined effects of human activity such as fisheries, aquaculture, wind energy, mining and maritime transport sectors on nature assets such as selected seaweed, invertebrate, fish habitats as well as bird and mammal species. The analyses showed that current Estonian maritime spatial planning will result in a moderate loss of some nature assets and a significant gain of benthic suspension feeders, although predicted losses in wind park areas can be mitigated if novel aquaculture activities such as mussel or macroalgal farming are established This test demonstrates how the PW4B tool can be used by planners to minimize adverse environmental effects, to suggest effective mitigation strategy, and to attain sustainable planning solutions.

Abstract Background Improving the quality and safety of perioperative care is a global priority. The Enhanced Peri-Operative Care for High-risk patients (EPOCH) trial was a stepped-wedge cluster randomised trial of a quality improvement (QI) programme to improve 90-day survival for patients undergoing emergency abdominal surgery in 93 hospitals in the UK National Health Service. Methods The aim of this process evaluation is to describe how the EPOCH intervention was planned, delivered and received, at both cluster and local hospital levels. The QI programme comprised of two interventions: a care pathway and a QI intervention to aid pathway implementation, focussed on stakeholder engagement, QI teamwork, data analysis and feedback and applying the model for improvement. Face-to-face training and online resources were provided to support senior clinicians in each hospital (QI leads) to lead improvement. For this evaluation, we collated programme activity data, administered an exit questionnaire to QI leads and collected ethnographic data in six hospitals. Qualitative data were analysed with thematic or comparative analysis; quantitative data were analysed using descriptive statistics. Results The EPOCH trial did not demonstrate any improvement in survival or length of hospital stay. Whilst the QI programme was delivered as planned at the cluster level, self-assessed intervention fidelity at the hospital level was variable. Seventy-seven of 93 hospitals responded to the exit questionnaire (60 from a single QI lead response on behalf of the team); 33 respondents described following the QI intervention closely (35%) and there were only 11 of 37 care pathway processes that > 50% of respondents reported attempting to improve. Analysis of qualitative data suggests QI leads were often attempting to deliver the intervention in challenging contexts: the social aspects of change such as engaging colleagues were identified as important but often difficult and clinicians frequently attempted to lead change with limited time or organisational resources. Conclusions Significant organisational challenges faced by QI leads shaped their choice of pathway components to focus on and implementation approaches taken. Adaptation causing loss of intervention fidelity was therefore due to rational choices made by those implementing change within constrained contexts. Future large-scale QI programmes will need to focus on dedicating local time and resources to improvement as well as on training to develop QI capabilities. EPOCH trial registration ISRCTN80682973 https://doi.org/10.1186/ISRCTN80682973 Registered 27 February 2014 and Lancet protocol 13PRT/7655.

Given the very recent investment in research on organic rabbit production, many knowledge gaps remain. Simulation models based on data from experiments and farms may help generate general principles for organic rabbit production. Our goals were to (i) develop a model to simulate intake regulation and growth of rabbits raised on pastures, (ii) validate this model under a diversity of conditions and (iii) conduct a simulation experiment to predict the potential to decrease the supply of complete feed by increasing the grazing area per rabbit. The model developed (PASTRAB) simulates organic rabbit fattening on pastures in four main submodels that represent dynamics of (i) herbage standing biomass, fill and feed values; (ii) intake of herbage, complementary feed (i.e. complete pellets, cereal–legume grain mixtures) and hay as regulated by herbage allowance, fill and feed values of feedstuffs and rabbit physiological parameters; (iii) conversion of rabbit intake into live weight gain; and (iv) rabbit mortality. The model also calculates gross margin per rabbit sold. Model accuracy was assessed by considering the fit between observed and predicted herbage intake, which was low, with a relative root mean square error (rRMSE) of 51% and 66% on grass-based and legume-based pastures, respectively. However, the standard deviations of observed herbage intake were similar to the root mean square error of predicted herbage intake, indicating that it would have been difficult to improve model calibration. The fit between observed and predicted rabbit live weight was acceptable, with an rRMSE of 11% and 10% for grass-based and legume-based pastures, respectively. Simulated scenarios showed that a decrease in complementary feed combined with an increase in the grazing area per rabbit had little impact on average daily growth and gross margin per rabbit but increased herbage use efficiency. With 90 g of complementary feed per day and grazing of 0.4 m²/rabbit per day, herbage use efficiency was 22%, with average daily growth of 21.6 g/day and gross margin of 18.80 €/rabbit. With no complementary feed and grazing of 1.2 m²/rabbit per day, average daily growth decreased (19.2 g/day), but herbage use efficiency reached 100% and gross margin reached 19.20 €/rabbit. We used PASTRAB in participatory workshops with farmers so that the latter could explore adaptations to their current practices. Overall, farmers considered the model predictions realistic, and some of them decided to adapt some of their management practices immediately after the workshops.

The performance of updated versions of the four earth system models (ESMs) CNRM, EC-Earth, HadGEM, and MPI-ESM is assessed in comparison to their predecessor versions used in Phase 5 of the Coupled Model Intercomparison Project. The Earth System Model Evaluation Tool (ESMValTool) is applied to evaluate selected climate phenomena in the models against observations. This is the first systematic application of the ESMValTool to assess and document the progress made during an extensive model development and improvement project. This study focuses on the South Asian monsoon (SAM) and the West African monsoon (WAM), the coupled equatorial climate, and Southern Ocean clouds and radiation, which are known to exhibit systematic biases in present-day ESMs. The analysis shows that the tropical precipitation in three out of four models is clearly improved. Two of three updated coupled models show an improved representation of tropical sea surface temperatures with one coupled model not exhibiting a double Intertropical Convergence Zone (ITCZ). Simulated cloud amounts and cloud–radiation interactions are improved over the Southern Ocean. Improvements are also seen in the simulation of the SAM and WAM, although systematic biases remain in regional details and the timing of monsoon rainfall. Analysis of simulations with EC-Earth at different horizontal resolutions from T159 up to T1279 shows that the synoptic-scale variability in precipitation over the SAM and WAM regions improves with higher model resolution. The results suggest that the reasonably good agreement of modeled and observed mean WAM and SAM rainfall in lower-resolution models may be a result of unrealistic intensity distributions.

Abstract Background Theobroma cacao L., native to the Amazonian basin of South America, is an economically important fruit tree crop for tropical countries as a source of chocolate. The first draft genome of the species, from a Criollo cultivar, was published in 2011. Although a useful resource, some improvements are possible, including identifying misassemblies, reducing the number of scaffolds and gaps, and anchoring un-anchored sequences to the 10 chromosomes. Methods We used a NGS-based approach to significantly improve the assembly of the Belizian Criollo B97-61/B2 genome. We combined four Illumina large insert size mate paired libraries with 52x of Pacific Biosciences long reads to correct misassembled regions and reduced the number of scaffolds. We then used genotyping by sequencing (GBS) methods to increase the proportion of the assembly anchored to chromosomes. Results The scaffold number decreased from 4,792 in assembly V1 to 554 in V2 while the scaffold N50 size has increased from 0.47 Mb in V1 to 6.5 Mb in V2. A total of 96.7% of the assembly was anchored to the 10 chromosomes compared to 66.8% in the previous version. Unknown sites (Ns) were reduced from 10.8% to 5.7%. In addition, we updated the functional annotations and performed a new RefSeq structural annotation based on RNAseq evidence. Conclusion Theobroma cacao Criollo genome version 2 will be a valuable resource for the investigation of complex traits at the genomic level and for future comparative genomics and genetics studies in cacao tree. New functional tools and annotations are available on the Cocoa Genome Hub ( http://cocoa-genome-hub.southgreen.fr ).

We describe Global Atmosphere 6.0 and Global Land 6.0 (GA6.0/GL6.0): the latest science configurations of the Met Office Unified Model and JULES (Joint UK Land Environment Simulator) land surface model developed for use across all timescales. Global Atmosphere 6.0 includes the ENDGame (Even Newer Dynamics for General atmospheric modelling of the environment) dynamical core, which significantly increases mid-latitude variability improving a known model bias. Alongside developments of the model's physical parametrisations, ENDGame also increases variability in the tropics, which leads to an improved representation of tropical cyclones and other tropical phenomena. Further developments of the atmospheric and land surface parametrisations improve other aspects of model performance, including the forecasting of surface weather phenomena. We also describe GA6.1/GL6.1, which includes a small number of long-standing differences from our main trunk configurations that we continue to require for operational global weather prediction. Since July 2014, GA6.1/GL6.1 has been used by the Met Office for operational global numerical weather prediction, whilst GA6.0/GL6.0 was implemented in its remaining global prediction systems over the following year.

A design strategy, referred to as behavior by design, was introduced to develop novel architectured materials starting from their expected stress-strain response. Target behaviors in this strategy have unusual shapes that provide new functions to the material. Here, a numerical toolbox was employed to predict the geometry of metal tensile samples with a corrugated gauge section, given the expected characteristics of their stress-strain response. A multiscale approach, based on a finite element model, was used to construct characteristic points and indices on the macroscopic stress-strain curves to select the relevant input geometrical parameters. Additive manufacturing (electron beam melting) was employed to build several predicted geometries in Ti-6Al-4V titanium alloy. Mechanical testing revealed a good agreement between the experimental and predicted behaviors with limited difference in strain (0.8%) and stress (50 MPa). Shape variations such as local thickness fluctuations were identified using X-ray tomography as a source of mismatch between simulations and experiments. The ability to control the whole shape of unusual stress-strain curves is expected to bring new exciting functionalities to architectured materials. Keywords: Behavior by design, Additive manufacturing, Architectured materials, Strain hardening, X-ray tomography

A community diagnostics and performance metrics tool for the evaluation of Earth system models (ESMs) has been developed that allows for routine comparison of single or multiple models, either against predecessor versions or against observations. The priority of the effort so far has been to target specific scientific themes focusing on selected essential climate variables (ECVs), a range of known systematic biases common to ESMs, such as coupled tropical climate variability, monsoons, Southern Ocean processes, continental dry biases, and soil hydrology–climate interactions, as well as atmospheric CO2 budgets, tropospheric and stratospheric ozone, and tropospheric aerosols. The tool is being developed in such a way that additional analyses can easily be added. A set of standard namelists for each scientific topic reproduces specific sets of diagnostics or performance metrics that have demonstrated their importance in ESM evaluation in the peer-reviewed literature. The Earth System Model Evaluation Tool (ESMValTool) is a community effort open to both users and developers encouraging open exchange of diagnostic source code and evaluation results from the Coupled Model Intercomparison Project (CMIP) ensemble. This will facilitate and improve ESM evaluation beyond the state-of-the-art and aims at supporting such activities within CMIP and at individual modelling centres. Ultimately, we envisage running the ESMValTool alongside the Earth System Grid Federation (ESGF) as part of a more routine evaluation of CMIP model simulations while utilizing observations available in standard formats (obs4MIPs) or provided by the user.

Organic agriculture is developing worldwide, and organic rabbit production has developed within this context. It entails raising rabbits in moving cages or paddocks, which enables them to graze grasslands. As organic farmers currently lack basic technical information, the objective of this article is to characterize herbage intake, feed intake and the growth rate of rabbits raised on grasslands in different environmental and management contexts (weather conditions, grassland type and complete feed supplementation). Three experiments were performed with moving cages at an experimental station. From weaning, rabbits grazed a natural grassland, a tall fescue grassland and a sainfoin grassland in experiments 1, 2 and 3, respectively. Rabbit diets were supplemented with a complete pelleted feed limited to 69 g dry matter (DM)/rabbit per day in experiment 1 and 52 g DM/rabbit per day in experiments 2 and 3. Herbage allowance and fiber, DM and protein contents, as well as rabbit intake and live weight, were measured weekly. Mean herbage DM intake per rabbit per day differed significantly (P

Purpose: The aim of this study is to establish which specific cognitive abilities are phenotypically related to reading skill in adolescence and determine whether this phenotypic correlation is explained by polygenetic overlap. Method: In an Australian population sample of twins and non-twin siblings of European ancestry (734 [less than or equal to] N [less than or equal to] 1542 [50.7% < F < 66%], mean age = 16.7, range = 11-28 years) from the Brisbane Adolescent Twin Study, mixed-effects models were used to test the association between a dyslexia polygenic score (based on genome-wide association results from a study of 51,800 dyslexics versus >1 million controls) and quantitative cognitive measures. The variance in the cognitive measure explained by the polygenic score was compared to that explained by a reading difficulties phenotype (scores that were lower than 1.5 SD below the mean reading skill) to derive the proportion of the association due to genetic influences. Results: The strongest phenotypic correlations were between poor reading and verbal tests R[superscript 2] up to 6.2%); visuo-spatial working memory was the only measure that did not show association with poor reading. Dyslexia polygenic scores could completely explain the phenotypic covariance between poor reading and most working memory tasks and were most predictive of performance on a test of arithmetic (R[superscript 2] = 2.9%). Conclusion: Shared genetic pathways are thus highlighted for the commonly found association between reading and mathematics abilities, and for the verbal short-term/working memory deficits often observed in dyslexia.

BackgroundCardiac troponin T (cTnT) is elevated after coronary artery bypass grafting surgery. The aim of this study was to determine the association between cTnT elevations between 6 and 12 hours after coronary artery bypass grafting and in‐hospital outcome. Methods and ResultsWe prospectively studied 1722 patients undergoing isolated coronary artery bypass grafting. We assessed the association between conventional cTnT (749 patients) and high‐sensitivity cTnT (hs‐cTnT; 973 patients) 6 to 12 hours postoperatively with in‐hospital major adverse cardiac or cerebrovascular events (MACCE), a composite of all‐cause death, myocardial infarction, or stroke. The prespecified secondary outcome was a safety composite of MACCE, resuscitation, intensive care unit readmission or admission ≥48 hours, inotrope or vasopressor use ≥24 hours, or new‐onset renal insufficiency. Among patients with a conventional cTnT measurement, 92 experienced a MACCE (12%) and 146 experienced a safety composite event (19%). Likewise, for hs‐cTnT, 114 experienced a MACCE (12%) and 153 experienced a safety composite event (16%). Compared with cTnT ≤200 ng/L, each 200‐ng/L increment in cTnT was associated with a monotonous increase in the odds of MACCE and the safety composite outcome. Conventional and hs‐cTnT demonstrated moderate discrimination for MACCE (areas under the fitted receiver operating characteristics curve, 0.72 and 0.77 for conventional and hs‐cTnT, respectively) and the safety composite outcome (areas under the fitted receiver operating characteristics curve, 0.66 and 0.74 for conventional and hs‐cTnT, respectively) and resulted in improved prognostic performance when added to the EuroSCORE. At a cutoff of 800 ng/L, conventional and hs‐cTnT provided clinically relevant power to rule in MACCE and the safety composite outcome. ConclusionscTnT levels assessed between 6 and 12 hours after coronary artery bypass grafting identify patients at increased risk of MACCE or other complications.

Statistical procedures are proposed to describe, compare and forecast the behaviour of seasonal variations in two daily price series of Canary tomato exported to German and British markets, respectively, over the last decade. These seasonal patterns are pseudo-periodic as the length of the seasonal period changes frequently in dependence of market conditions. Seasonal effect at a day in the harvesting period is defined as a spline function of the proportion of the length of such a period elapsed up to such a day. Then, seasonal patterns for the two series are compared in terms of the area between the corresponding spline functions. The ability of these models to capture the dynamic process of change in the seasonal pattern is useful to forecasting purpose. Furthermore, an analytical tool is also proposed to obtain forecasts of the seasonal pattern in one of these two series from the forecasts of the seasonal pattern in the other one. These procedures are useful for farmers in developing strategies related to the seasonal distribution of tomato production exported to each market.

Modulating bile acid synthesis has long been considered a good strategy by which to improve cholesterol homeostasis in humans. The farnesoid X receptor (FXR), the key regulator of bile acid synthesis, was, therefore, identified as an interesting target for drug discovery. We compared the effect of four, structurally unrelated, synthetic FXR agonists in two fat-fed rodent species and observed that the three most potent and selective agonists decreased plasma cholesterol in LDL receptor-deficient (Ldlr −/−) mice, but none did so in hamsters. Detailed investigation revealed increases in the expression of small heterodimer partner (Shp) in their livers and of intestinal fibroblast growth factor 15 or 19 (Fgf15/19) in mice only. Cyp7a1 expression and fecal bile acid (BA) excretion were strongly reduced in mice and hamsters by all four FXR agonists, whereas bile acid pool sizes were reduced in both species by all but the X-Ceptor compound in hamsters. In Ldlr −/− mice, the predominant bile acid changed from cholate to the more hydrophilic β-muricholate due to a strong repression of Cyp8b1 and increase in Cyp3a11 expression. However, FXR agonists caused only minor changes in the expression of Cyp8b1 and in bile acid profiles in hamsters. In summary, FXR agonist-induced decreases in bile acid pool size and lipophilicity and in cholesterol absorption and synthesis could explain the decreased plasma cholesterol in Ldlr −/− mice. In hamsters, FXR agonists reduced bile acid pool size to a smaller extent with minor changes in bile acid profile and reductions in sterol absorption, and consequently, plasma cholesterol was unchanged.

We describe here the development and evaluation of an Earth system model suitable for centennial-scale climate prediction. The principal new components added to the physical climate model are the terrestrial and ocean ecosystems and gas-phase tropospheric chemistry, along with their coupled interactions. The individual Earth system components are described briefly and the relevant interactions between the components are explained. Because the multiple interactions could lead to unstable feedbacks, we go through a careful process of model spin up to ensure that all components are stable and the interactions balanced. This spun-up configuration is evaluated against observed data for the Earth system components and is generally found to perform very satisfactorily. The reason for the evaluation phase is that the model is to be used for the core climate simulations carried out by the Met Office Hadley Centre for the Coupled Model Intercomparison Project (CMIP5), so it is essential that addition of the extra complexity does not detract substantially from its climate performance. Localised changes in some specific meteorological variables can be identified, but the impacts on the overall simulation of present day climate are slight. This model is proving valuable both for climate predictions, and for investigating the strengths of biogeochemical feedbacks.

It is claimed that apoA-I expression is repressed in mice by cholic acid (CA) and its taurine conjugate, taurocholic acid (TCA) via farnesoid X receptor (FXR) activation. We measured apoA-I expression in mice, hamsters, and rats treated with highly potent and selective synthetic FXR agonists or with TCA. All of the synthetic agonists bound to FXR with high affinity in a scintillation proximity assay. However, TCA did not compete with the radioligand up to the highest concentration used (100 μM). The C-site regulatory region of apoA-I, through which FXR has been reported to regulate its expression, is completely conserved across the species investigated. In both male and female human apoA-I-transgenic mice, we reproduced the previously reported strong inhibition of human apoA-I expression upon treatment with the typical supraphysiological dose of TCA used in such studies. However, in contrast to some previous reports, TCA did not repress murine apoA-I expression in the same mice. Also, more-potent and -selective FXR agonists did not affect human or murine apoA-I expression in this model. In LDL receptor-deficient mice and Golden Syrian hamsters, selective FXR agonists did not affect apoA-I expression, whereas in Wistar rats, some even increased apoA-I expression. In conclusion, selective FXR agonists do not repress apoA-I expression in rodents. Repression of human apoA-I expression by TCA in transgenic mice is probably mediated through FXR-independent mechanisms.

Spoligotyping was used to examine IS6110-positive DNA of 26 Mycobacterium bovis, M. bovis BCG and M. bovis subsp. caprae non-viable isolates stored up to 10 years. All of these isolates were previously identified by biochemical tests and all 17/17 tested isolates were earlier found virulent for guinea pigs. In total seven spoligotypes, designated S1-S7, were detected and compared with the spoligotypes of 3 176 isolates in the database of the National Institute of Public Health and the Environment (RIVM) in Bilthoven, the Netherlands. A Neotype M. bovis strain, isolated in 1965 in the USA and thereafter stored in The Czechoslovak National Collection of Type Cultures (My 310/87) since 1987 was of an identical spoligotype S4 with the original reference M. bovis strain from the USA. The M. bovis isolates from capybara's (Hydrochoerus hydrochaeris) imported from Germany to the Czech Republic in 1989, as well as cattle isolates from 1966, 1991 and 1994, were of the most common type S1. Also a human isolate from 1981, a M. bovis BCG vaccine strain and clinical M. bovis BCG isolates from three children with post-vaccinal complications were of this most predominant spoligotype. e four unique spoligotypes S2, S3, S5 and S6 were identified in M. bovis isolates from cattle in the years 1965, 1996 and 1967 in the CzechRepublic, respectively, but also in isolates from farmed red deer (Cervus elaphus) from 1991 and in cattle isolates from Slovakia from the year 1992. The scarcely occurring spoligotype S7, which is typical for M. b. caprae was detected in the Czech Republic from farmed red deer (1999), cattle isolates (1966, 1991, 1995) and in a strain isolated from an 80-year-old man (1999). Several strains isolated in each of three outbreaks in cattle herds were examined. Identical spoligotypes were detected in two outbreaks and different causal agents (M. bovis of spoligotype S1 and M. b. caprae of spoligotype S7) were identified in two cows from the third outbreak. e results confirm an effective control of bovine tuberculosis in the CzechRepublic and Slovakia during 1959-1968, because previously circulating spoligotypes were successfully eradicated. e data also suggest other reservoirs of bovine tuberculosis may exist among free-living wild animals.

Molecular biology methods offer new opportunities to differentiate, identify and type bacterial species and strains. These methods use the variability of nucleic sequences of genes such as 16S rDNA, beta subunit RNA-ase (rpoB), gyrase (gyrB), rDNA internal transcribed spacer and other genes. The aim of this paper is to provide comprehensive information about the methods available to differentiate and identify species of mycobacteria at the DNA sequence level. The methods discussed in the review include PCR, PCR-REA, sequencing analysis, spoligotyping and DNA fingerprinting. These methods have been applied to both the "universal" part of the genome and to specific mycobacterial genes.

The St. Thomas' mixed hyperlipidemic (SMHL) rabbit (previously St. Thomas' Hospital rabbit) is a putative model of familial combined hyperlipidemia (FCH). When fed a low (0.08%) cholesterol diet, it exhibits elevations in both plasma cholesterol and triglyceride compared to New Zealand White (NZW) controls. To determine the mechanism for this hyperlipidemia we studied the secretion of apolipoprotein B (apoB)-containing lipoproteins from perfused livers of both young and mature rabbits. During a 3-h perfusion we measured the total cholesterol and triglyceride content of the medium and the cholesterol, triglyceride, and apoB content of very low density lipoprotein (VLDL)1 (Sf 60–400), VLDL2 (Sf 20–60), intermediate (Sf 12–20), and low (Sf 0–12) density lipoproteins (IDL, LDL). Lipoprotein concentrations increased linearly throughout the perfusion period. The rate of cholesterol output was 3-fold higher (459 vs. 137 ng/g liver/min, P = 0.003) in SMHL versus NZW rabbits whilst that of triglyceride was similar (841 vs. 662 ng/g liver/min, NS). VLDL1 cholesterol output was elevated 2-fold (232 vs. 123 ng/g liver/min, P < 0.05) and VLDL2 + IDL + LDL cholesterol output, 4.5-fold (106 vs. 23 ng/g liver/min, P < 0.005) in SMHL versus NZW rabbits. ApoB output in VLDL1 was 38 ng/g liver per min in SMHL and 14 ng/g liver per min in NZW (NS). In SMHL VLDL2 + IDL + LDL apoB was increased 9-fold at 53 versus 6 ng/g liver per min in NZW (P < 0.001). We conclude that the SMHL rabbit overproduces apoB-containing lipoproteins particularly in the VLDL2 + IDL + LDL fraction, a characteristic consistent with its use as a model of FCH.—Ardern, H. A., G. M. Benson, K. E. Suckling, M. J. Caslake, J. Shepherd, and C. J. Packard. Apolipoprotein B overproduction by the perfused liver of the St. Thomas' mixed hyperlipidemic (SMHL) rabbit.

Bromodeoxyuridine incorporation is a useful method for studying the pattern of DNA synthesis in proliferating cells. The distribution pattern of incorporated BrdU in villus enterocytes of duodenal explants was analysed after exposure to TNFα in organ culture. TNFα caused a consistent, low level uptake of BrdU in the portion of the nucleus close to the nuclear membrane, this pattern was absent from the control cultures. As these epithelial cells are terminally arrested in G0, the BrdU incorporation was thought not to be due to S phase DNA synthesis, but rather a response to the cytotoxic influence of TNFα. Microtitre plate proliferation assays of cell density and DNA synthesis were devised to study the effects of TNFα on confluent monolayers of the human foetal jejunal cell line I407 and the mouse fibrosarcoma cell line L929. Both cell lines showed a similar response to TNFα. Exposure to TNFα alone did not reduce cell numbers but did cause a significant increase in DNA synthesis (p < 0.05). When cycloheximtde was added in tandem with TNFα there was a significant reduction in cell number (p < 0.001) and level of DNA synthesis (p < 0.01) indicative of cell death. The DNA of cells exposed to TNFα and cycloheximide was fragmented when viewed on an electrophoresis gel. The results show that BrdU incorporation might be a good indicator of damage to the DNA of cells after cytotoxic insult. TNFα may be responsible for villus enterocyte damage in enteropathies such as coeliac disease and GVHR of the small bowel.