Origins of concentration dependence of waiting times for single-molecule fluorescence binding

Binary fluorescence time series obtained from single-molecule imaging experiments can be used to infer protein binding kinetics, in particular, association and dissociation rate constants from waiting time statistics of fluorescence intensity changes. In many cases, rate constants inferred from fluorescence time series exhibit nonintuitive dependence on ligand concentration. Here we examine several possible mechanistic and technical origins that may induce ligand dependence of rate constants. Using aggregated Markov models, we show under the condition of detailed balance that non-fluorescent bindings and missed events due to transient interactions, instead of conformation fluctuations, may underly the dependence of waiting times and thus apparent rate constants on ligand concentrations. In general, waiting times are rational functions of ligand concentration. The shape of concentration dependence is qualitatively affected by the number of binding sites in the single molecule and is quantitatively tuned by model parameters. We also show that ligand dependence can be caused by non-equilibrium conditions which result in violations of detailed balance and require an energy source. As to a different but significant mechanism, we examine the effect of ambient buffers that can substantially reduce the effective concentration of ligands that interact with the single molecules. To demonstrate the effects by these mechanisms, we applied our results to analyze the concentration dependence in a single-molecule experiment EGFR binding to fluorophore-labeled adaptor protein Grb2 by Morimatsu et al. (PNAS,104:18013,2007).Comment: 11 pages, 4 figures; J. Chem. Phys., 137, 201

Saturated locally optimal designs under differentiable optimality criteria

We develop general theory for finding locally optimal designs in a class of single-covariate models under any differentiable optimality criterion. Yang and Stufken [Ann. Statist. 40 (2012) 1665-1681] and Dette and Schorning [Ann. Statist. 41 (2013) 1260-1267] gave complete class results for optimal designs under such models. Based on their results, saturated optimal designs exist; however, how to find such designs has not been addressed. We develop tools to find saturated optimal designs, and also prove their uniqueness under mild conditions.Comment: Published in at http://dx.doi.org/10.1214/14-AOS1263 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Higher Education: a once-in-a-lifetime purchase

Purpose - Drawing on infrequent purchase and university selection literature, this study aims to make theoretical contributions to the identification and comprehension of the ‘once-in-a-lifetime purchase’ (OILP) phenomenon. Design/methodology/approach - Data derived from in-depth interviews with 34 Taiwanese and 11 Chinese students over two phases suggest that an OILP qualitatively differs from other purchases. Findings - The principal traits of OILP are quadripartite in character: zero-repurchase intention; permanency of purchase; high social pressure; and extensive information search. The results contribute to theoretical understanding of the higher education (HE) sector as one type of OILP provider, and managerial implications are discussed specifically for HE institutions. Practical implications - Marketing managers of HE institutions should be cognisant of the range of information collected by prospective OILP customers from a variety of different sources. Prospective students who are OILP customers perceive non-marketing information as more reliable than marketing promotional materials and will better assist them during their decision making.Originality/value - The paper makes explicit theoretical and instrumental contributions to our identification and comprehension of the OILP phenomenon, shedding new light on studies of consumer purchase decision literature. It also extends previous understanding of HE marketing by showing that choosing an HE degree is, in fact, an OILP and, as such, requires a new way of approaching prospective students as consumers

Are There Any Best Practices for Developing Gen Y/Young Professionals?

According to U.S. Census Data, each year 1 million Millennials enter the workforce; nearly 40 percent of the U.S. workforce will be Millennials by 2020. Characterized as remarkably different from Baby Boomers, Gen Y is facing many challenges when it comes to leadership roles. Gen Y leaders are expected to refocus organizations as global forces, develop cultural intelligence, develop strategic thinking and decision-making intelligence, and nurture long-term collaboration.2 Development programs specifically designed for Millennials are necessary to fill the gaps, and are powerful tools for attracting and retaining top young professionals

Yang-Mills Instantons from Gravitational Instantons

We show that every gravitational instantons are SU(2) Yang-Mills instantons on a Ricci-flat four manifold although the reverse is not necessarily true. It is shown that gravitational instantons satisfy exactly the same self-duality equation of SU(2) Yang-Mills instantons on the Ricci-flat manifold determined by the gravitational instantons themselves. We explicitly check the correspondence with several examples and discuss their topological properties.Comment: v3; 38 pages, version to appear in JHE