Internal protein dynamics shifts the distance to the mechanical transition state

Mechanical unfolding of polyproteins by force spectroscopy provides valuable insight into their free energy landscapes. Most experiments of the unfolding process have been fit to two-state and/or one dimensional models, with the details of the protein and its dynamics often subsumed into a zero-force unfolding rate and a distance x(u)(1D) to the transition state. We consider the entire phase space of a model protein under a constant force, and show that x(u)(1D) contains a sizeable contribution from exploring the full multidimensional energy landscape. This effect is greater for proteins with many degrees of freedom that are affected by force; and surprisingly, we predict that externally attached flexible linkers also contribute to the measured unfolding characteristics

Hospital Costs of Colorectal Cancer Care

Objective In a hospital based setting, identify factors which influence the cost of colorectal cancer care? Design Retrospective case note review Setting Nottingham, United Kingdom Participants 227 patients treated for colorectal cancer Methods Retrospective review of the hospital records provided the primary data for the costing study and included all CRC related resource consumption over the study period. Results Of 700 people identified, 227 (32%) sets of hospital notes were reviewed. The median age of the study group was 70.3 (IQR 11.3) years and there were 128 (56%) males. At two years, there was a significant difference in costs between Dukes D cancers (£3641) and the other stages (£3776 Dukes A; £4921 Dukes B). Using univariate and multivariate regression, the year of diagnosis, Dukes stage of disease, intensive nursing care, stoma requirements and recurrent disease all significantly affected the total cost of care. Conclusions CRC remains costly with no significant difference in costs if diagnosed before compared to after 1992. Very early and very late stage cancers remain the least costly stage of cancers to treat. Other significant effectors of hospital costs were the site of cancer (rectal), intensive nursing care, recurrent disease and the need for a stoma

Development of a novel 3D simulation modelling system for distributed manufacturing

This paper describes a novel 3D simulation modelling system for supporting our distributed machine design and control paradigm with respect to simulating and emulating machine behaviour on the Internet. The system has been designed and implemented using Java2D and Java3D. An easy assembly concept of drag-and-drop assembly has been realised and implemented by the introduction of new connection features (unified interface assembly features) between two assembly components (modules). The system comprises a hierarchical geometric modeller, a behavioural editor, and two assemblers. During modelling, designers can combine basic modelling primitives with general extrusions and integrate CAD geometric models into simulation models. Each simulation component (module) model can be visualised and animated in VRML browsers. It is reusable. This makes machine design re-configurable and flexible. A case study example is given to support our conclusions

A framework of web-based conceptual design

A web-based conceptual design prototype system is presented. The system consists of four parts which interpret on-line sketches as 2D and 3D geometry, extract 3D hierarchical configurations, allow editing of component behaviours, and produce VRML-based behavioural simulations for design verification and web-based application. In the first part, on-line freehand sketched input is interpreted as 2D and 3D geometry, which geometrically represents conceptual design. The system then infers 3D configuration by analysing 3D modelling history. The configuration is described by a parent–child hierarchical relationship and relative positions between two geometric components. The positioning information is computed with respect to the VRML97 specification. In order to verify the conceptual design of a product, the behaviours can be specified interactively on different components. Finally, the system creates VRML97 formatted files for behavioural simulation and collaborative design application over the Internet. The paper gives examples of web-based applications. This work forms a part of a research project into the design and establishing of modular machines for automation manufacture. A consortium of leading automotive companies is collaborating on the research project

The microwave induced resistance response of a high mobility 2DEG from the quasi-classical limit to the quantum Hall regime

Microwave induced resistance oscillations (MIROs) were studied experimentally over a very wide range of frequencies ranging from ~20 GHz up to ~4 THz, and from the quasi-classical regime to the quantum Hall effect regime. At low frequencies regular MIROs were observed, with a periodicity determined by the ratio of the microwave to cyclotron frequencies. For frequencies below 150 GHz the magnetic field dependence of MIROs waveform is well described by a simplified version of an existing theoretical model, where the damping is controlled by the width of the Landau levels. In the THz frequency range MIROs vanish and only pronounced resistance changes are observed at the cyclotron resonance. The evolution of MIROs with frequency are presented and discussed.Comment: 4 pages, presented at EP2DS, to be published in Physica

Challenges of open innovation: the paradox of firm investment in open-source software

Open innovation is a powerful framework encompassing the generation, capture, and employment of intellectual property at the firm level. We identify three fundamental challenges for firms in applying the concept of open innovation: finding creative ways to exploit internal innovation, incorporating external innovation into internal development, and motivating outsiders to supply an ongoing stream of external innovations. This latter challenge involves a paradox, why would firms spend money on R&D efforts if the results of these efforts are available to rival firms? To explore these challenges, we examine the activity of firms in opensource software to support their innovation strategies. Firms involved in open-source software often make investments that will be shared with real and potential rivals. We identify four strategies firms employ – pooled R&D/product development, spinouts, selling complements and attracting donated complements – and discuss how they address the three key challenges of open innovation. We conclude with suggestions for how similar strategies may apply in other industries and offer some possible avenues for future research on open innovation

Probing exotic phenomena at the interface of nuclear and particle physics with the electric dipole moments of diamagnetic atoms: A unique window to hadronic and semi-leptonic CP violation

The current status of electric dipole moments of diamagnetic atoms which involves the synergy between atomic experiments and three different theoretical areas -- particle, nuclear and atomic is reviewed. Various models of particle physics that predict CP violation, which is necessary for the existence of such electric dipole moments, are presented. These include the standard model of particle physics and various extensions of it. Effective hadron level combined charge conjugation (C) and parity (P) symmetry violating interactions are derived taking into consideration different ways in which a nucleon interacts with other nucleons as well as with electrons. Nuclear structure calculations of the CP-odd nuclear Schiff moment are discussed using the shell model and other theoretical approaches. Results of the calculations of atomic electric dipole moments due to the interaction of the nuclear Schiff moment with the electrons and the P and time-reversal (T) symmetry violating tensor-pseudotensor electron-nucleus are elucidated using different relativistic many-body theories. The principles of the measurement of the electric dipole moments of diamagnetic atoms are outlined. Upper limits for the nuclear Schiff moment and tensor-pseudotensor coupling constant are obtained combining the results of atomic experiments and relativistic many-body theories. The coefficients for the different sources of CP violation have been estimated at the elementary particle level for all the diamagnetic atoms of current experimental interest and their implications for physics beyond the standard model is discussed. Possible improvements of the current results of the measurements as well as quantum chromodynamics, nuclear and atomic calculations are suggested.Comment: 46 pages, 19 tables and 16 figures. A review article accepted for EPJ

SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness

A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the coronavirus disease 2019 (COVID-19) global pandemic. Structural studies have led to the development of mutations that stabilize Betacoronavirus spike proteins in the prefusion state, improving their expression and increasing immunogenicity1. This principle has been applied to design mRNA-1273, an mRNA vaccine that encodes a SARS-CoV-2 spike protein that is stabilized in the prefusion conformation. Here we show that mRNA-1273 induces potent neutralizing antibody responses to both wild-type (D614) and D614G mutant2 SARS-CoV-2 as well as CD8+ T cell responses, and protects against SARS-CoV-2 infection in the lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a phase III trial to evaluate its efficacy