Stoichiometries and Affinities of Interacting Proteins from Concentration Series of Solution Scattering Data: Decomposition by Least Squares and Quadratic Optimization

In studying interacting proteins, complementary insights are provided by analyzing both the association model (the stoichiometry and affinity constants of the intermediate and final complexes) and the quaternary structure of the resulting complexes. Many current methods for analyzing protein interactions either give a binary answer to the question of association and no information about quaternary structure or at best provide only part of the complete picture. Presented here is a method to extract both types of information from X-ray or neutron scattering data for a series of equilibrium mixtures containing the initial components at different concentrations. The method determines the association pathway and constants, along with the scattering curves of the individual members of the mixture, so as to best explain the scattering data for the mixtures. The derived curves then enable reconstruction of the intermediate and final complexes. Using simulated solution scattering data for four hetero-oligomeric complexes with different structures, molecular weights and association models, it is demonstrated that this method accurately determines the simulated association model and scattering profiles for the initial components and complexes. Recognizing that experimental mixtures contain static contaminants and nonspecific complexes with the lowest affinities (inter-particle interference) as well as the desired specific complex(es), a new analytical method is also employed to extend this approach to evaluating the association models and scattering curves in the presence of static contaminants, testing both a nonparticipating monomer and a large homo-oligomeric aggregate. It is demonstrated that the method is robust to both random noise and systematic noise from such contaminants, and the treatment of nonspecific complexes is discussed. Finally, it is shown that this method is applicable over a large range of weak association constants typical of specific but transient protein-protein complexes

-Adrenergic Receptor Stimulation Transactivates Protease-Activated Receptor 1 via Matrix Metalloproteinase 13 in Cardiac Cells

Chronic β-adrenergic receptor (β-AR) overstimulation, a hallmark of heart failure, is associated with increased cardiac expression of matrix metalloproteinases (MMPs). MMP-1 has been shown to cleave and activate the protease-activated receptor 1 (PAR1) in non-cardiac cells. Here, we hypothesized that β-AR stimulation would result in MMP-dependent PAR1 transactivation in cardiac cells

Deciphering the mechanism of O2 reduction with electronically tunable non-heme iron enzyme model complexes

A homologous series of electronically tuned 2,20,200-nitrilotris(N-arylacetamide) pre-ligands (H3LR) were prepared (R ¼ NO2, CN, CF3, F, Cl, Br, Et, Me, H, OMe, NMe2) and some of their corresponding Fe and Zn species synthesized. The iron complexes react rapidly with O2, the final products of which are diferric mu-oxo bridged species. The crystal structure of the oxidized product obtained from DMA solutions contain a structural motif found in some diiron proteins. The mechanism of iron mediated O2 reduction was explored to the extent that allowed us to construct an empirically consistent rate law. A Hammett plot was constructed that enabled insightful information into the rate-determining step and hence allows for a differentiation between two kinetically equivalent O2 reduction mechanisms

A timeband framework for modelling real-time systems

Complex real-time systems must integrate physical processes with digital control, human operation and organisational structures. New scientific foundations are required for specifying, designing and implementing these systems. One key challenge is to cope with the wide range of time scales and dynamics inherent in such systems. To exploit the unique properties of time, with the aim of producing more dependable computer-based systems, it is desirable to explicitly identify distinct time bands in which the system is situated. Such a framework enables the temporal properties and associated dynamic behaviour of existing systems to be described and the requirements for new or modified systems to be specified. A system model based on a finite set of distinct time bands is motivated and developed in this paper

The opposites task: Using general rules to test cognitive flexibility in preschoolers

A brief narrative description of the journal article, document, or resource. Executive functions play an important role in cognitive development, and during the preschool years especially, children's performance is limited in tasks that demand flexibility in their behavior. We asked whether preschoolers would exhibit limitations when they are required to apply a general rule in the context of novel stimuli on every trial (the "opposites" task). Two types of inhibitory processing were measured: response interference (resistance to interference from a competing response) and proactive interference (resistance to interference from a previously relevant rule). Group data show 3-year-olds have difficulty inhibiting prepotent tendencies under these conditions, whereas 5-year-olds' accuracy is near ceiling in the task. (Contains 4 footnotes and 1 table.

Evidence and Ideology in Macroeconomics: The Case of Investment Cycles

The paper reports the principal findings of a long term research project on the description and explanation of business cycles. The research strongly confirmed the older view that business cycles have large systematic components that take the form of investment cycles. These quasi-periodic movements can be represented as low order, stochastic, dynamic processes with complex eigenvalues. Specifically, there is a fixed investment cycle of about 8 years and an inventory cycle of about 4 years. Maximum entropy spectral analysis was employed for the description of the cycles and continuous time econometrics for the explanatory models. The central explanatory mechanism is the second order accelerator, which incorporates adjustment costs both in relation to the capital stock and the rate of investment. By means of parametric resonance it was possible to show, both theoretically and empirically how cycles aggregate from the micro to the macro level. The same mathematical tool was also used to explain the international convergence of cycles. I argue that the theory of investment cycles was abandoned for ideological, not for evidential reasons. Methodological issues are also discussed

The On-Orbit Performance of the Galaxy Evolution Explorer

We report the first year on-orbit performance results for the Galaxy Evolution Explorer (GALEX), a NASA Small Explorer that is performing a survey of the sky in two ultraviolet bands. The instrument comprises a 50 cm diameter modified Ritchey-Chretien telescope with a 1.25 degree field of view, selectable imaging and objective grism spectroscopic modes, and an innovative optical system with a thin-film multilayer dichroic beam splitter that enables simultaneous imaging by a pair of photon counting, microchannel plate, delay line readout detectors. Initial measurements demonstrate that GALEX is performing well, meeting its requirements for resolution, efficiency, astrometry, bandpass definition and survey sensitivity.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issu

Fecal occult blood and fecal calprotectin as point-of-care markers of intestinal morbidity in Ugandan children with Schistosoma mansoni infection.

BACKGROUND: Calprotectin is a calcium-binding cytoplasmic protein found in neutrophils and increasingly used as a marker of bowel inflammation. Fecal occult blood (FOB) is also a dependable indicator of bowel morbidity. The objective of our study was to determine the applicability of these tests as surrogate markers of Schistosoma mansoni intestinal morbidity before and after treatment with praziquantel (PZQ). METHODS: 216 children (ages 3-9 years old) from Buliisa District in Lake Albert, Uganda were examined and treated with PZQ at baseline in October 2012 with 211 of them re-examined 24 days later for S. mansoni and other soil transmitted helminths (STH). POC calprotectin and FOB assays were performed at both time points on a subset of children. Associations between the test results and infection were analysed by logistic regression. RESULTS: Fecal calprotectin concentrations of 150-300 µg/g were associated with S. mansoni egg patent infection both at baseline and follow up (OR: 12.5 P = 0.05; OR: 6.8 P = 0.02). FOB had a very strong association with baseline anemia (OR: 9.2 P = 0.03) and medium and high egg intensity schistosomiasis at follow up (OR: 6.6 P = 0.03; OR: 51.3 P = 0.003). Both tests were strongly associated with heavy intensity S. mansoni infections. There was a significant decrease in FOB and calprotectin test positivity after PZQ treatment in those children who had egg patent schistosomiasis at baseline. CONCLUSIONS: Both FOB and calprotectin rapid assays were found to correlate positively and strongly with egg patent S. mansoni infection with a positive ameloriation response after PZQ treatment indicative of short term reversion of morbidity. Both tests were appropriate for use in the field with excellent operational performance and reliability. Due to its lower-cost which makes its scale-up of use affordable, FOB could be immediately adopted as a monitoring tool for PC campaigns for efficacy evaluation before and after treatment

Thioglycosides Are Efficient Metabolic Decoys of Glycosylation that Reduce Selectin Dependent Leukocyte Adhesion

© 2018 Elsevier Ltd Small-molecule inhibitors of glycosylation can be applied in basic science studies, and clinical investigations as anti-inflammatory, anti-metastatic, and anti-viral therapies. This article demonstrates that thioglycosides represent a class of potent metabolic decoys that resist hydrolysis, and block E-selectin-dependent leukocyte adhesion in models of inflammation