A cell-permeable biscyclooctyne as a novel probe for the identification of protein sulfenic acids

Reactive oxygen species act as important second messengers in cell signaling and homeostasis through the oxidation of protein thiols. However, the dynamic nature of protein oxidation and the lack of sensitivity of existing molecular probes have hindered our understanding of such reactions; therefore, new tools are required to address these challenges. We designed a bifunctional variant of the strained bicyclo[6.1.0]nonyne (BCN-E-BCN) that enables the tagging of intracellular protein sulfenic acids for biorthogonal copper-free click chemistry. In validation studies, BCN-E-BCN binds the sulfenylated form of the actin-severing protein cofilin, while mutation of the cognate cysteine residues abrogates its binding. BCN-E-BCN is cell permeable and reacts rapidly with cysteine sulfenic acids in cultured cells. Using different azide-tagged conjugates, we demonstrate that BCN-E-BCN can be used in various applications for the detection of sulfenylated proteins. Remarkably, cycloaddition of an azide-tagged fluorophore to BCN-E-BCN labelled proteins produced in vivo can be visualized by fluorescence microscopy to reveal their subcellular localization. These findings demonstrate a novel and multifaceted approach to the detection and trapping of sulfenic acids

Perspectives on the Missiological Legacy of Martin Luther and the Protestant Reformation

Upon the occasion of the 500th anniversary Martin Luther’s publication of his 95 theses, this composite article brings together five perspectives on the missiological legacy of the reformer and the subsequent Protestant Reformation. The blend of voices makes clear that Luther and the subsequent Protestant Reformation do not have a simple missiological legacy but rather various legacies: theological, ecclesiological, political, and practical; some of which co-exist, and even collide, in the same ecclesiastical community. The scandalous legacy of a splintered and splintering church remains. Yet, demonstrations of mutual recognition, reciprocal respect, and genuine fellowship can be found in certain missiological circles

Quantifying Downstream, Vertical and Lateral Variation in Fluvial Deposits : Implications From the Huesca Distributive Fluvial System

Acknowledgments Author Ben Martin thanks the University of Glasgow for providing funding for this project through the ‘Stressed Environments’ scholarship fund. The SAFARI consortium (https://safaridb.com/home) are thanked for providing virtual outcrop models that have been analyzed within this paper. Two anonymous reviewers are thanked for their thorough and constructive comments on this paper.Peer reviewedPublisher PD

Optical sparse telescope arrays and scintillation noise

Fresnel propagation of starlight after it passes through high altitude turbulence in the Earth’s atmosphere results in random fluctuations of the intensity at ground level, known as scintillation. This effect adds random noise to photometric measurements with ground-based optical telescopes. Spatial correlation of the intensity fluctuations means that the fractional photometric noise due to scintillation may be substantially smaller for a sparse array of small aperture telescopes than for a single large aperture of the same total area. Assuming that the photometric noise for each telescope is independent, averaging the light curves measured by N telescopes reduces the noise by a factor of N−−√⁠. For example, for bright stars, the signal-to-noise ratio of a 2.54 m telescope can be achieved for an array of thirty 20 cm telescopes if the scintillation noise measured for each telescope is uncorrelated. In this paper, we present results from simulation and from observations at the Isaac Newton Telescope. These explore the impact that several parameters have on the measured correlation of the scintillation noise between neighbouring telescopes. We show that there is significant correlation between neighbouring telescopes with separations parallel to the wind direction of the dominant high altitude turbulent layer. We find that the telescopes in an array should be separated by at least twice their aperture diameter so that there is negligible correlation of the photometric noise. We discuss additional benefits of using sparse telescope arrays, including reduced cost and increased field of view

To Err is Normable: The Computation of Frequency-Domain Error Bounds from Time-Domain Data

This paper exploits the relationships among the time-domain and frequency-domain system norms to derive information useful for modeling and control design, given only the system step response data. A discussion of system and signal norms is included. The proposed procedures involve only simple numerical operations, such as the discrete approximation of derivatives and integrals, and the calculation of matrix singular values. The resulting frequency-domain and Hankel-operator norm approximations may be used to evaluate the accuracy of a given model, and to determine model corrections to decrease the modeling errors

Devise: a framework for the evaluation of internet search engines

This project investigates the feasibility of the use of user-satisfaction as a multidimensional evaluative construct of search engines. Search engine developments are reviewed to reveal a range of indexing and retrieval techniques that may assist casual users in the information retrieval task. Yet few evaluation studies have considered the impact of system features, in particular those with which the user interacts for search assistance. A broad review of retrieval system evaluation highlights the complex environment in which measures of both the utility of the search results and the usability of the system are sought from a user-perspective. Our proposed approach for a user-centered evaluation is based on a conceptual framework in which user-satisfaction is characterised as a variable dependent on system features and functions and expressed in a moderating context of user-task requirement. Towards this end, the research reported here focuses on the definition of the construct of user satisfaction on the multi dimensions of the retrieval process, an expression of what a typical user is trying to do. Empirical work was then undertaken to test the feasibility and potential value of the implementation of the framework for the evaluation of three search engines. Initial results are presented which provide a degree of understanding of how users are satisfied and on what criteria. This provides the basis on which we make recommendations for the refinement of the multidimensional framework and its use as a methodology for the evaluation of search engines from a user perspective

An Emergency Room Decision-Support Program That Increased Physician Office Visits, Decreased Emergency Room Visits, and Saved Money

The objective of this study was to evaluate an Emergency Room having a Decision-Support (ERDS) program designed to appropriately reduce ER use among frequent users, defined as 3 or more visits within a 12-month period. To achieve this, adults with an AARP Medicare Supplement Insurance plan insured by UnitedHealthcare Insurance Company (for New York residents, UnitedHealthcare Insurance Company of New York) were eligible to participate in the program. These included 7070 individuals who elected to enroll in the ERDS program and an equal number of matched nonparticipants who were eligible but either declined or were unreachable. Program-related benefits were estimated by comparing the difference in downstream health care utilization and expenditures between engaged and not engaged individuals after using propensity score matching to adjust for case mix differences between these groups. As a result, compared with the not engaged, engaged individuals experienced better care coordination, evidenced by a greater reduction in ER visits (P=0.033) and hospital admissions (P=0.002) and an increase in office visits (P<0.001). The program was cost-effective, with a return on investment (ROI) of 1.24, which was calculated by dividing the total program savings ($3.41 million) by the total program costs ($2.75 million). The ROI implies that for every dollar invested in this program, $1.24 was saved, most of which was for the federal Medicare program. In conclusion, the decrease in ER visits and hospital admissions and the increase in office visits may indicate the program helped individuals to seek the appropriate levels of care. (Population Health Management 2014;17:257?264)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140184/1/pop.2013.0117.pd