An in silico study of the molecular basis of B-RAF activation and conformational stability

<p>Abstract</p> <p>Background</p> <p>B-RAF kinase plays an important role both in tumour induction and maintenance in several cancers and it is an attractive new drug target. However, the structural basis of the B-RAF activation is still not well understood.</p> <p>Results</p> <p>In this study we suggest a novel molecular basis of B-RAF activation based on molecular dynamics (MD) simulations of B-RAF^WTand the B-RAF^V600E, B-RAF^K601Eand B-RAF^D594Vmutants. A strong hydrogen bond network was identified in B-RAF^WTin which the interactions between Lys601 and the well known catalytic residues Lys483, Glu501 and Asp594 play an important role. It was found that several mutations, which directly or indirectly destabilized the interactions between these residues within this network, contributed to the changes in B-RAF activity.</p> <p>Conclusion</p> <p>Our results showed that the above mechanisms lead to the disruption of the electrostatic interactions between the A-loop and the αC-helix in the activating mutants, which presumably contribute to the flipping of the activation segment to an active form. Conversely, in the B-RAF^D594Vmutant that has impaired kinase activity, and in B-RAF^WTthese interactions were strong and stabilized the kinase inactive form.</p

Total cost of ownership as a tool for inter-firm cost management: a case in the Belgian utilities industry.

In today's environment, communicating what your products and services are worth to customers' business has never been more important. Customers increasingly look at purchasing as a way to increase profits and to reduce costs. To persuade customers to focus on the total costs rather than simply on acquisition price, a supplier must have an accurate understanding of what his customers value. In this case study, we demonstrate how a utility supplier performed a Total Cost of Ownership analysis for one of his customers. The case study offers insights in how an inter-firm Total Cost of Ownership analysis can be beneficial to the buyer as well as to the supplier by optimising and better coordinating the performance of operations across the value chain and by facilitating further initiatives to intensify the buyer-supplier relationship.Product; Purchasing; Costs; Cost; Value; Case studies; Studies; Utilities; Performance; Management; Industry;

Widening access in selection using situational judgement tests: evidence from the UKCAT

CONTEXT Widening access promotes student diversity and the appropriate representation of all demographic groups. This study aims to examine diversity-related benefits of the use of situational judgement tests (SJTs) in the UK Clinical Aptitude Test (UKCAT) in terms of three demographic variables: (i) socioeconomic status (SES); (ii) ethnicity, and (iii) gender. METHODS Outcomes in medical and dental school applicant cohorts for the years 2012 (n = 15 581) and 2013 (n = 15 454) were studied. Applicants' scores on cognitive tests and an SJT were linked to SES (parents' occupational status), ethnicity (White versus Black and other minority ethnic candidates), and gender. RESULTS Firstly, the effect size for SES was lower for the SJT (d = 0.13-0.20 in favour of the higher SES group) than it was for the cognitive tests (d = 0.38-0.35). Secondly, effect sizes for ethnicity of the SJT and cognitive tests were similar (d = similar to 0.50 in favour of White candidates). Thirdly, males outperformed females on cognitive tests, whereas the reverse was true for SJTs. When equal weight was given to the SJT and the cognitive tests in the admission decision and when the selection ratio was stringent, simulated scenarios showed that using an SJT in addition to cognitive tests might enable admissions boards to select more students from lower SES backgrounds and more female students. CONCLUSIONS The SJT has the potential to appropriately complement cognitive tests in the selection of doctors and dentists. It may also put candidates of lower SES backgrounds at less of a disadvantage and may potentially diversify the student intake. However, use of the SJT applied in this study did not diminish the role of ethnicity. Future research should examine these findings with other SJTs and other tests internationally and scrutinise the causes underlying the role of ethnicity

Separating the classical and quantum information via quantum cloning

An application of quantum cloning to optimally interface a quantum system with a classical observer is presented, in particular we describe a procedure to perform a minimal disturbance measurement on a single qubit by adopting a 1->2 cloning machine followed by a generalized measurement on a single clone and the anti-clone or on the two clones. Such scheme has been applied to enhance the transmission fidelity over a lossy quantum channel.Comment: 4 pages, 2figure

Experimental demonstration of coherent state estimation with minimal disturbance

We investigate the optimal tradeoff between information gained about an unknown coherent state and the state disturbance caused by the measurement process. We propose several optical schemes that can enable this task, and we implement one of them, a scheme which relies on only linear optics and homodyne detection. Experimentally we reach near optimal performance, limited only by detection inefficiencies. In addition we show that such a scheme can be used to enhance the transmission fidelity of a class of noisy channels

Assessment of the Building Situation Tool adoption among firefighters

Abstract. Technology and technical tools have become standard resources that first responders use in their work. Throughout an incident, technology serves to improve communications, planning, safety, situational awareness, and decision-making. Certain incidents require specialized tools to resolve the crisis, whether it is for the law enforcement, medical, or firefighter unit to manage. One under-utilized technology is building sensors, recording information on temperature, CO2, smoke, airflow, and movement in the building. While modern buildings include sensors to monitor for potential dangers, that information is not shared with the fire department beyond notification of a fire alert. Despite the considerable number of hardware and software solutions adopted, firefighters in Kainuu, Finland still rely on paper plans when examining indoor disasters. The Building Situation Tool (BUST) was developed to utilize the building sensors and visualize the building as a 3D model, to provide firefighters with a realtime overview of the site during emergencies. The purpose of this study is to investigate the technological competencies of firefighters, determine the usability and ease of use of BUST, and examine the factors that influence the adoption of BUST. The constructs of the Technology Acceptance Model (TAM), selfefficacy, and workplace learning are used. These three constructs provide insight into how the intention to use technology is modeled, how users perceive their knowledge and use of technology, and how the workplace influences learning and performance. A mixed-method approach was used in this study. The firefighter’s technology self-efficacy, perceived usefulness, and ease of were recorded through quantitative questionnaires. The firefighter’s experiences in using the technology and factors that influence adoption were recorded through a questionnaire and interview. The findings show a sufficient level of competency, that first-time users prefer guided instructions, clarity in the user interface, controls, and options to customize the user interface. The findings have practical implications for the future development of BUST and its adoption in the workflow of firefighters