A quantitative model of the initiation of DNA replication in Saccharomyces cerevisiae predicts the effects of system perturbations.

BackgroundEukaryotic cell proliferation involves DNA replication, a tightly regulated process mediated by a multitude of protein factors. In budding yeast, the initiation of replication is facilitated by the heterohexameric origin recognition complex (ORC). ORC binds to specific origins of replication and then serves as a scaffold for the recruitment of other factors such as Cdt1, Cdc6, the Mcm2-7 complex, Cdc45 and the Dbf4-Cdc7 kinase complex. While many of the mechanisms controlling these associations are well documented, mathematical models are needed to explore the network's dynamic behaviour. We have developed an ordinary differential equation-based model of the protein-protein interaction network describing replication initiation.ResultsThe model was validated against quantified levels of protein factors over a range of cell cycle timepoints. Using chromatin extracts from synchronized Saccharomyces cerevisiae cell cultures, we were able to monitor the in vivo fluctuations of several of the aforementioned proteins, with additional data obtained from the literature. The model behaviour conforms to perturbation trials previously reported in the literature, and accurately predicts the results of our own knockdown experiments. Furthermore, we successfully incorporated our replication initiation model into an established model of the entire yeast cell cycle, thus providing a comprehensive description of these processes.ConclusionsThis study establishes a robust model of the processes driving DNA replication initiation. The model was validated against observed cell concentrations of the driving factors, and characterizes the interactions between factors implicated in eukaryotic DNA replication. Finally, this model can serve as a guide in efforts to generate a comprehensive model of the mammalian cell cycle in order to explore cancer-related phenotypes

The Quantum Socket: Three-Dimensional Wiring for Extensible Quantum Computing

Quantum computing architectures are on the verge of scalability, a key requirement for the implementation of a universal quantum computer. The next stage in this quest is the realization of quantum error correction codes, which will mitigate the impact of faulty quantum information on a quantum computer. Architectures with ten or more quantum bits (qubits) have been realized using trapped ions and superconducting circuits. While these implementations are potentially scalable, true scalability will require systems engineering to combine quantum and classical hardware. One technology demanding imminent efforts is the realization of a suitable wiring method for the control and measurement of a large number of qubits. In this work, we introduce an interconnect solution for solid-state qubits: The quantum socket. The quantum socket fully exploits the third dimension to connect classical electronics to qubits with higher density and better performance than two-dimensional methods based on wire bonding. The quantum socket is based on spring-mounted micro wires the three-dimensional wires that push directly on a micro-fabricated chip, making electrical contact. A small wire cross section (~1 mmm), nearly non-magnetic components, and functionality at low temperatures make the quantum socket ideal to operate solid-state qubits. The wires have a coaxial geometry and operate over a frequency range from DC to 8 GHz, with a contact resistance of ~150 mohm, an impedance mismatch of ~10 ohm, and minimal crosstalk. As a proof of principle, we fabricated and used a quantum socket to measure superconducting resonators at a temperature of ~10 mK.Comment: Main: 31 pages, 19 figs., 8 tables, 8 apps.; suppl.: 4 pages, 5 figs. (HiRes figs. and movies on request). Submitte

Electron impact excitation cross sections for allowed transitions in atoms

We present a semiempirical Gaunt factor for widely used Van Regemorter formula [Astrophys. J. 136, 906 (1962)] for the case of allowed transitions in atoms with the LS coupling scheme. Cross sections calculated using this Gaunt factor agree with measured cross sections to within the experimental error.Comment: RevTeX, 3 pages, 10 PS figures, 2 PS tables, submitted to Phys. Rev.

What next for Shared Lives? Family-based support as a potential option for older people

With an ageing population and limited resources the challenge for policy makers and practitioners is how best to provide for the care and support needs of older people. This article draws on findings from two studies, a scoping study of the personalisation of care services and another which aimed to generate evidence about the potential use of family-based support schemes (Shared Lives, SL) for certain groups of older people. Forty-three schemes participated in a survey to gather information about services provided and the extent to which this included older people and their carers, and six staffs were interviewed across two schemes about issues for expanding provision for older people in their local areas. It was evident that SL schemes were already supporting a number of older people and there was support for expansion from both schemes and local authorities. Adequate resources, awareness raising, management commitment, and a pool of suitable carers would be needed to support any expansion effort. There is also still a need for SL to be more widely known and understood by care managers if it is to be considered part of mainstream provision for older people

The art of being human : a project for general philosophy of science

Throughout the medieval and modern periods, in various sacred and secular guises, the unification of all forms of knowledge under the rubric of ‘science’ has been taken as the prerogative of humanity as a species. However, as our sense of species privilege has been called increasingly into question, so too has the very salience of ‘humanity’ and ‘science’ as general categories, let alone ones that might bear some essential relationship to each other. After showing how the ascendant Stanford School in the philosophy of science has contributed to this joint demystification of ‘humanity’ and ‘science’, I proceed on a more positive note to a conceptual framework for making sense of science as the art of being human. My understanding of ‘science’ is indebted to the red thread that runs from Christian theology through the Scientific Revolution and Enlightenment to the Humboldtian revival of the university as the site for the synthesis of knowledge as the culmination of self-development. Especially salient to this idea is science‘s epistemic capacity to manage modality (i.e. to determine the conditions under which possibilities can be actualised) and its political capacity to organize humanity into projects of universal concern. However, the challenge facing such an ideal in the twentyfirst century is that the predicate ‘human’ may be projected in three quite distinct ways, governed by what I call ‘ecological’, ‘biomedical’ and ‘cybernetic’ interests. Which one of these future humanities would claim today’s humans as proper ancestors and could these futures co-habit the same world thus become two important questions that general philosophy of science will need to address in the coming years

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

Knowledge-based energy functions for computational studies of proteins

This chapter discusses theoretical framework and methods for developing knowledge-based potential functions essential for protein structure prediction, protein-protein interaction, and protein sequence design. We discuss in some details about the Miyazawa-Jernigan contact statistical potential, distance-dependent statistical potentials, as well as geometric statistical potentials. We also describe a geometric model for developing both linear and non-linear potential functions by optimization. Applications of knowledge-based potential functions in protein-decoy discrimination, in protein-protein interactions, and in protein design are then described. Several issues of knowledge-based potential functions are finally discussed.Comment: 57 pages, 6 figures. To be published in a book by Springe

A Proposal for a Three Detector Short-Baseline Neutrino Oscillation Program in the Fermilab Booster Neutrino Beam

A Short-Baseline Neutrino (SBN) physics program of three LAr-TPC detectors located along the Booster Neutrino Beam (BNB) at Fermilab is presented. This new SBN Program will deliver a rich and compelling physics opportunity, including the ability to resolve a class of experimental anomalies in neutrino physics and to perform the most sensitive search to date for sterile neutrinos at the eV mass-scale through both appearance and disappearance oscillation channels. Using data sets of 6.6e20 protons on target (P.O.T.) in the LAr1-ND and ICARUS T600 detectors plus 13.2e20 P.O.T. in the MicroBooNE detector, we estimate that a search for muon neutrino to electron neutrino appearance can be performed with ~5 sigma sensitivity for the LSND allowed (99% C.L.) parameter region. In this proposal for the SBN Program, we describe the physics analysis, the conceptual design of the LAr1-ND detector, the design and refurbishment of the T600 detector, the necessary infrastructure required to execute the program, and a possible reconfiguration of the BNB target and horn system to improve its performance for oscillation searches.Comment: 209 pages, 129 figure

A randomised control trial of atorvastatin in bronchiectasis patients infected with <i>Pseudomonas aeruginosa</i>- a proof of concept study

Introduction: There are no randomised control trials of statin therapy in patients with severe bronchiectasis, chronically infected with Pseudomonas aeruginosa.Methods: 32 patients chronically infected with P. aeruginosa were recruited in this double blind cross over RCT. 16 patients were recruited in each arm, given atorvastatin 80mg or placebo for 3months, followed by a washout period for 6weeks, crossed over and administered the alternative therapy for 3months.Results: 27 patients completed the study. Atorvastatin did not significantly improve the primary endpoint of cough as measured by Leicester Cough Questionnaire [mean difference=1.92, 95% CI for difference (-0.57, 4.41), p=0.12]. However, atorvastatin treatment resulted in improved St Georges Respiratory Questionnaire (-5.62points, p=0.016), reduced serum CXCL8 (p=0.04), TNF (p=0.01) and ICAM1 (p=0.04). There was a trend towards improvement in serum CRP and serum neutrophil counts (p=0.07 and p=0.06 respectively). In vitro, we demonstrated that atorvastatin 10μM reduced fMLF induced upregulation of CD11b expression and changes in calcium flux reflecting an ability to decrease neutrophil activation.Conclusion: We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in bronchiectasis patients infected with P. aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation.</p