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How did human societies evolve from small groups, integrated by face-to-face cooperation, to huge anonymous societies of today, typically organized as states? Why is there so much variation in the ability of different human populations to construct viable states? Existing theories are usually formulated as verbal models and, as a result, do not yield sharply defined, quantitative predictions that could be unambiguously tested with data. Here we develop a cultural evolutionary model that predicts where and when the largest-scale complex societies arose in human history. The central premise of the model, which we test, is that costly institutions that enabled large human groups to function without splitting up evolved as a result of intense competition between societies-primarily warfare. Warfare intensity, in turn, depended on the spread of historically attested military technologies (e.g., chariots and cavalry) and on geographic factors (e.g., rugged landscape). The model was simulated within a realistic landscape of the Afroeurasian landmass and its predictions were tested against a large dataset documenting the spatiotemporal distribution of historical large-scale societies in Afroeurasia between 1,500 BCE and 1,500 CE. The model-predicted pattern of spread of large-scale societies was very similar to the observed one. Overall, the model explained 65% of variance in the data. An alternative model, omitting the effect of diffusing military technologies, explained only 16% of variance. Our results support theories that emphasize the role of institutions in state-building and suggest a possible explanation why a long history of statehood is positively correlated with political stability, institutional quality, and income per capita.

We have designed and developed a data integration and visualization platform that provides evidence about the association of known and potential drug targets with diseases. The platform is designed to support identification and prioritization of biological targets for follow-up. Each drug target is linked to a disease using integrated genome-wide data from a broad range of data sources. The platform provides either a target-centric workflow to identify diseases that may be associated with a specific target, or a disease-centric workflow to identify targets that may be associated with a specific disease. Users can easily transition between these target- and disease-centric workflows. The Open Targets Validation Platform is accessible at https://www.targetvalidation.org.

Summary ProtVista is a comprehensive visualization tool for the graphical representation of protein sequence features in the UniProt Knowledgebase, experimental proteomics and variation public datasets. The complexity and relationships in this wealth of data pose a challenge in interpretation. Integrative visualization approaches such as provided by ProtVista are thus essential for researchers to understand the data and, for instance, discover patterns affecting function and disease associations. Availability and Implementation ProtVista is a JavaScript component released as an open source project under the Apache 2 License. Documentation and source code are available at http://ebi-uniprot.github.io/ProtVista/. Supplementary information Supplementary data are available at Bioinformatics online.

Tuning and stacking approaches have been used to compile non-annually resolved peatland palaeo-water table records in several studies. This approach has been proposed as a potential way forward to overcome the chronological problems that beset the correlation of records and may help in the upscaling of palaeoclimate records for climate model-data comparisons. This paper investigates the uncertainties in this approach using a published water table compilation from Northern Ireland. Firstly, three plausible combinations of chronological match points are used to assess the variability of the reconstructions. It is apparent that even with markedly different match point combinations, the compilations are highly similar, especially when a 100-year running mean line is used for interpretation. Secondly, sample-specific reconstruction errors are scaled in relation to the standardised water table units and illustrated on the compiled reconstruction. Thirdly, the total chronological errors for each reconstruction are calculated using Bayesian age-modelling software. Although tuning and stacking approaches may be suitable for compiling peat-based palaeoclimate records, it is important that the reconstruction and chronological errors are acknowledged and clearly illustrated in future studies. The tuning of peat-based proxy climate records is based on a potentially flawed assumption that events are synchronous between sites.

The aim of this study was to evaluate pharmacokinetic and subjective responses to a prototype nicotine pyruvate (NP) aerosol generation system. In nine healthy adult daily cigarette smokers, plasma nicotine levels and subjective responses were assessed after double-blind administration of 10 inhalations of: NP (10 μg/puff, 20 μg/puff, and 30 μg/puff); Nicotrol/Nicorette nicotine vapor inhaler (NV) cartridge; and placebo (room air). Plasma nicotine concentrations increased to a significantly greater extent after inhalations of 20 μg/puff or 30 μg/puff NP (by 5.0 ± 3.4 ng/ml and 8.3 ± 3.1 ng/ml) than after placebo and NV conditions. Satisfaction ratings were higher for all NP conditions than for placebo, and harshness/irritation was lower for the NP 20 condition than for the NV control condition. Pulmonary function showed no adverse changes. These results demonstrate that NP inhalations produce rapid increases in plasma nicotine concentrations, provide satisfaction and are well tolerated. At the 20 μg/puff dose, peak nicotine concentrations were higher than with the Nicotrol/Nicorette nicotine vapor inhaler cartridge. Further trials of this promising nicotine inhalation technology are warranted to assess its safety and efficacy in smoking cessation treatment or harm reduction approaches.

OBJECTIVES: Haemodilution during cardiopulmonary bypass is associated with increased perioperative blood transfusions and is thought to reduce intraoperative oxygen delivery to the brain. We sought to evaluate our method of rapid antegrade prime displacement in the context of the perioperative blood transfusion rate, intraoperative cerebral saturations and postoperative hospital stay. METHODS: Retrospective analysis of 160 propensity-matched patients undergoing elective coronary artery bypass grafting was performed comparing different perfusion strategies on perioperative blood transfusion and length of postoperative stay. Eighty patients who had rapid antegrade prime displacement and vacuum-assisted venous drainage (RAD-VAD) were compared with 80 patients who had conventional cardiopulmonary bypass with gravity drainage (CB). RAD-VAD involved displacing all or most of the prime in the circuit with the patient’s own blood prior to the initiation of cardiopulmonary bypass within a 15–20 s window. Within each group, 10 patients had intraoperative cerebral saturation measurements. RESULTS: There were no differences in the baseline characteristics between the groups. Both groups had a significant fall (P< 0.05) in haematocrit during cardiopulmonary bypass from preoperative values, however, the fall in haematocrit was significantly less in the RADVAD group (P< 0.05). There was significantly (P< 0.05) less intraoperative and postoperative homologous blood transfusions in the RADVAD group (47.892 ml ± 8.14 and 76.58 ml ± 21.58) compared with the CB group (229.06 ml ± 105.03 and 199.91 ml ± 47.13). There was a significant fall in cerebral saturations within both groups (P< 0.05) but it was not significant between the groups. The postoperative stay was significantly (P< 0.05) shorter in the RAD-VAD group compared with the conventional group (7.74 days ± 0.51 vs 10.13 days ± 0.95). CONCLUSIONS: RAD-VAD is associated with a significantly lower blood transfusion rate perioperatively and shorter hospital stays compared with CB.

This paper presents a complex model transformation that takes two related UML models as input (class diagrams and state machines) and outputs an integrated formal model. The transformation is achieved using the Epsilon model management framework and has involved the definition of new CSP and B metamodels. The target model is a CSPB specification (a fusion of CSP and B) that can be used to analyse the source UML. Through a comparative study we conclude that the code written using Epsilon is more concise than the equivalent model-to-text transformation achieved using the iUML toolset.

Much research work has been done on linking UML and formal methods but few have focused on using formal methods to check the integrity of UML models so that the models can be verified. A current collaborative project between the University of Surrey and AWE plc is investigating the underpinning of xUML platform independent models with CSP || B specifications. Our position paper presents an overview of the project and demonstrates an opportunity for applying formal methods in industry. One of the project's aims is to support reasoning about concurrent xUML state machines. xUML is a subset of UML which provides support for code generation. AWE has already developed mappings between xUML and SPARK Ada and our current work will provide further techniques in order to ensure the safety of their software systems. UML has become the language of choice for systems engineers at AWE and support for formal techniques is necessary.

Tahiti field in deepwater Gulf of Mexico is a three-way anticlinal structure trapped against salt, with primary hydrocarbon-bearing turbidite sands ranging from 24,000 to 27,000 ft TVD. The discovery well was drilled in 2002, and two appraisal wells were drilled soon afterwards. Due to significant uncertainties remaining after appraisal, probabilistic methods were used to assess development alternatives.In this study the classical experimental design method was applied and reasonable P10, P50 and P90 reservoir simulation models were designed. Next, we looked upon the development plan by performing a second round of design of experiment runs with uncontrollable uncertainties and decisions as factors. The goal was to validate that the previously selected models reasonably represented P10, P50 and P90 oil recoveries and net present value after including decisions in the design. The validation worked out properly reinforcing the confidence in the model selection. Finally, the polynomial response models were used to explore multiple scenarios by varying decisions across the whole range of uncontrollable uncertainties.The proposed workflow enhances the use of experimental design by combining the technique with response surface methods and rational engineering judgment. The approach is recommended for the evaluation of greenfields when a new perspective of the economic analysis of project decisions is desired.

We describe the development of an IR source capable of generating light simultaneously in the 3-4 micrometers and 8-13 micrometers bands. Using a tandem optical parametric oscillator architecture, the output wavelengths arise as the signal and idler, respectively, of an AgGaSe2 based OPO. Both efficiency and tuning of this OPO system are discussed and, in particular, a rapid electrooptic method of tuning both mid-wave and long wave IR bands is described.© (1999) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

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