Backbone NMR resonance assignment of the Abelson kinase domain in complex with imatinib

Imatinib (Glivec or Gleevec) potently inhibits the tyrosine kinase activity of BCR-ABL, a constitutively activated kinase, which causes chronic myelogenous leukemia (CML). Here we report the first almost complete backbone assignment of c-ABL kinase domain in complex with imatini

Conditioned variation in heart rate during static breath-holds in the bottlenose dolphin (Tursiops truncatus)

Funding for this project was provided by the Office of Naval Research to AF (ONR Award # N00014-16-1-3088).Previous reports suggested the existence of direct somatic motor control over heart rate (fH) responses during diving in some marine mammals, as the result of a cognitive and/or learning process rather than being a reflexive response. This would be beneficial for O2 storage management, but would also allow ventilation-perfusion matching for selective gas exchange, where O2 and CO2 can be exchanged with minimal exchange of N2. Such a mechanism explains how air breathing marine vertebrates avoid diving related gas bubble formation during repeated dives, and how stress could interrupt this mechanism and cause excessive N2 exchange. To investigate the conditioned response, we measured the fH-response before and during static breath-holds in three bottlenose dolphins (Tursiops truncatus) when shown a visual symbol to perform either a long (LONG) or short (SHORT) breath-hold, or during a spontaneous breath-hold without a symbol (NS). The average fH (ifHstart), and the rate of change in fH (difH/dt) during the first 20 s of the breath-hold differed between breath-hold types. In addition, the minimum instantaneous fH (ifHmin), and the average instantaneous fH during the last 10 s (ifHend) also differed between breath-hold types. The difH/dt was greater, and the ifHstart, ifHmin, and ifHend were lower during a LONG as compared with either a SHORT, or an NS breath-hold (P < 0.05). Even though the NS breath-hold dives were longer in duration as compared with SHORT breath-hold dives, the difH/dt was greater and the ifHstart, ifHmin, and ifHend were lower during the latter (P < 0.05). In addition, when the dolphin determined the breath-hold duration (NS), the fH was more variable within and between individuals and trials, suggesting a conditioned capacity to adjust the fH-response. These results suggest that dolphins have the capacity to selectively alter the fH-response during diving and provide evidence for significant cardiovascular plasticity in dolphins.Publisher PDFPeer reviewe

Disabled architects: Unlocking the potential for practice

Abstract Disabled Architects: Unlocking the Potential for PracticeSandra Manley, Ann de Graft-Johnson and Katie Lucking, UWE, BristolThe Royal Institute of British Architects (RIBA) commissioned UWE to investigate the experiences of disabled architects and architecture students with the aim of making recommendations to increase the diversity of the profession and disseminate good practice. Architects for Change (AFC), the RIBA’s Equality and Diversity forum and the RIBA Inclusive Design Working Group promoted the research ambitions. The core aims of the research were to:•Identify good practice relating to equal opportunities for disabled people in the architecture profession; •Identify obstacles to entrance, progression and retention of disabled people in architecture;•Assess the current situation and make recommendations for improvement against which future progress can be monitored;Key conclusions from the findings were that:•the architecture profession needs to make significant changes; •in particular the educational environment needs to change to be more inclusive;•some students were traumatised by their educational experiences. Nevertheless most disabled people who participated in the study retained their enthusiasm to the practice of architecture. In the words of one student who participated: “Architecture is a marvelously stimulating field. Learning about it is a privilege” (Architecture Student, 2010).The report recommendations were based on the findings and included primary and secondary education as well as higher education, the relevant professional bodies and architects practices

Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia

A case study showing how the determination of multiple cocrystal structures of the protein tyrosine kinase c-Abl was used to support drug discovery, resulting in a compound effective in the treatment of chronic myelogenous leukaemia

The U.S. Arctic Observing Viewer: A Web-Mapping Application for Enhancing Environmental Observation of the Changing Arctic

Although much progress has been made with various Arctic Observing efforts, assessing that progress can be difficult. What data collection efforts are established or underway? Where? By whom? To help meet the strategic needs of programs such as the U.S. Study of Environmental Arctic Change (SEARCH), the Arctic Observing Network (AON), Sustaining Arctic Observing Networks (SAON) and related initiatives, an update has been released for the Arctic Observing Viewer (AOV; http://ArcticObservingViewer.org). This web mapping application and information system has begun to compile the who, what, where, and when for thousands of data collection sites (such as boreholes, ship tracks, buoys, towers, sampling stations, sensor networks, vegetation sites, stream gauges, and observatories) wherever marine, terrestrial, or atmospheric data are collected. Contributing partners for this collaborative resource include the U.S. NSF, ACADIS, ADIwg, AOOS, a2dc, AON, ARMAP, BAID, CAFF, IASOA, INTERACT, and others. While focusing on U.S. activities, the AOV welcomes information exchange with international groups for mutual benefit. Users can visualize, navigate, select, search, draw, print, and more. AOV is founded on principles of interoperability, with open metadata and web service standards, so that agencies and organizations can use AOV tools and services for their own purposes. In this way, AOV will reinforce and complement other distributed yet interoperable cyber-resources and will help science planners, funding agencies, researchers, data specialists, and others to assess status, identify overlap, fill gaps, optimize sampling design, refine network performance, clarify directions, access data, coordinate logistics, collaborate, and more in order to meet Arctic Observing goals.Malgré les progrès réalisés dans le cadre de nombreux efforts d’observation de l’Arctique, les progrès peuvent être difficiles à évaluer. Quelles initiatives de collecte de données sont en cours ou sont établies? À quel endroit? Et qui gère ces initiatives? Pour aider à répondre aux besoins stratégiques de programmes comme ceux de l’organisme américain Study of Environmental Arctic Change (SEARCH), du réseau Arctic Observing Network (AON), des réseaux Sustaining Arctic Observing Networks (SAON) et d’autres programmes connexes, on a procédé à la mise à jour de l’Arctic Observing Viewer (AOV; http://ArcticObservingViewer.org). Ce système d’information jumelé à une application de mappage sur le Web a amorcé la compilation des coordonnées et des renseignements se rapportant à des milliers de sites de collecte de données (comme les trous de forage, les trajets de navires, les bouées, les tours, les stations d’échantillonnage, les réseaux de capteurs, les sites de végétation, les fluviomètres et les observatoires) où des données marines, terrestres ou atmosphériques sont prélevées. Parmi les partenaires qui collaborent à cette ressource, notons U.S. NSF, ACADIS, ADIwg, AOOS, a2dc, AON, ARMAP, BAID, CAFF, IASOA, INTERACT et d’autres encore. Bien que l’AOV se concentre sur les activités américaines, il accepte l’échange d’information avec des groupes internationaux lorsqu’il existe des avantages mutuels. Les utilisateurs peuvent visualiser les données, naviguer dans le système, faire des sélections et des recherches, dessiner, imprimer et ainsi de suite. L’AOV fonctionne moyennant des principes d’interopérabilité, avec des métadonnées ouvertes et des normes de service sur le Web afin que les organismes et les organisations puissent utiliser les outils et les services de l’AOV pour leurs propres fins. De cette façon, l’AOV sera en mesure de consolider et de compléter d’autres cyberressources à la fois réparties et interopérables, en plus d’aider les planificateurs de la science, les bailleurs de fonds, les chercheurs, les spécialistes des données et d’autres encore à évaluer les statuts, à repérer les dédoublements, à combler les écarts, à optimiser les plans d’échantillonnage, à raffiner le rendement des réseaux, à clarifier les consignes, à accéder aux données, à coordonner la logistique, à collaborer et ainsi de suite afin de répondre aux objectifs d’observation de l’Arctique

Deleted in Liver Cancer 2 (DLC2) Was Dispensable for Development and Its Deficiency Did Not Aggravate Hepatocarcinogenesis

DLC2 (deleted in liver cancer 2), a Rho GTPase-activating protein, was previously shown to be underexpressed in human hepatocellular carcinoma and has tumor suppressor functions in cell culture models. We generated DLC2-deficient mice to investigate the tumor suppressor role of DLC2 in hepatocarcinogenesis and the function of DLC2 in vivo. In this study, we found that, unlike homologous DLC1, which is essential for embryonic development, DLC2 was dispensable for embryonic development and DLC2-deficient mice could survive to adulthood. We also did not observe a higher incidence of liver tumor formation or diethylnitrosamine (DEN)-induced hepatocarcinogenesis in DLC2-deficient mice. However, we observed that DLC2-deficient mice were smaller and had less adipose tissue than the wild type mice. These phenotypes were not due to reduction of cell size or defect in adipogenesis, as observed in the 190B RhoGAP-deficient mouse model. Together, these results suggest that deficiency in DLC2 alone does not enhance hepatocarcinogenesis

Machine learning algorithms performed no better than regression models for prognostication in traumatic brain injury

Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury. Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified. Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study. Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches